text:
Cytotoxic activities of cucurbitane-type triterpene glycosides 15′–28'.
\r\n\tThis book is intended to provide a series of peer reviewed chapters that the guest editor believe will aid in increasing the quality of the research focus across the growing field of grain and seeds compound functionality research. Overall, the objective of this project is to serve as a reference book and as an excellent resource for students, researchers, and scientists interested and working in different functional aspects of grain and seed compounds, and particularly for the scientific community to encourage it to continue publishing their research findings on grain and seed and to provide basis for new research, and the area of sustainable crop production.
Industrial carbon-bearing waste from airliners, trains, cars, boats, turbine blades, sporting, industrial and commercial goods is very hard to recycle or reshape into original components [1, 2]. Carbon fibre-reinforced polymers (CFRPs) (>90% carbon) contain significant fraction of carbon fibres within a polymer matrix, along with varying levels of additives such as silica, alumina and other minerals. Carbon fibres contribute towards high tensile strength, whereas the matrix provides the impact strength [3]. Their key characteristics such as long-term thermal stability, rigidity, dimensional stability, resistance to creep and deformation under load, high electrical and thermal insulating properties and other advantages play an important role in their various applications; however, these create major bottlenecks for their end-of-use disposal [4, 5]. These fire-resistant materials that are designed to resist combustion contain large amounts of pure, disordered carbon with a complex bond network and are difficult to recycle by conventional means.
Aeronautics is one of the biggest consumers of CFRPs due to the recent developments in planes, for example, Boeing 787, Airbus A380 and A350, whereas the growth in the automotive sector is somewhat slow. According to the International Civil Aviation Organisation, the global air transport network has been observed to double in size every 15 years. It is estimated that ~44% of the global fleet of commercial, military and private aircrafts is likely to reach end of life in 20 years or so; between 400 and 600 commercial aircraft are disassembled around the world each year [6]. A cost-effective environmentally sustainable management of large volumes of CFRPs' waste from end-of-life products therefore assumes great significance and urgency.
Protecting the environment for future generations is a fundamental issue and a great challenge; manufacturers are seeking alternatives approaches of waste management. Key challenge is to find environmentally friendly, alternative recycling approaches and to transform carbon-bearing composite waste into valuable resources. Recycling rates for CFRPs are currently very low, with most of the waste ending up in landfills. While landfilling is a relatively cheap and convenient disposal route, environmental legislation on waste management is also becoming increasingly restrictive.
According to the European Union's Waste Framework Directive [7], landfilling is the least preferred waste management option. Landfilling carbon-bearing waste can be a serious environmental hazard as well. It can lead to the release of greenhouse gases, including huge amounts CO2 and methane; up to 50% of these emissions are of methane, which is 21 times more potent a greenhouse gas than CO2. Manufacturers across Europe are required to pay to dispose their production waste if it goes to landfill as well as a climate change levy.
Current approaches for recycling composite materials, reuse and material recovery from waste CFRPs are briefly reviewed in the following section. While several techniques such as pyrolysis, solvolysis, mechanical grinding, chemical, high voltage fragmentation and so on using different approaches have shown feasibility of recycling, commercial/industrial applications of recycled carbon fibres are still very limited. Recycled fibres are generally of lower quality as compared to virgin fibres due to lack of control in fibre length and length distribution, diminished surface quality and multiple sources [8].
Recycling is profitable and sustainable only if the value of the reclaimed materials exceeds the cost of the recycling process. Recycled carbon fibres can be 30–40% cheaper than virgin carbon fibres; however, the degradation of fibre characteristics can be a serious issue during reuse. Process conditions are known to vary significantly depending on the waste CFRP products being recycled. Composite waste, generally sourced across different industries, is also likely to be heterogeneous in nature. A new approach based on using waste CFRPs as a carbon resource in steelmaking will be presented, especially for those CFRPs that cannot be transformed back in to carbon fibres.
Various approaches for recycling and reusing waste CFRPs as carbon fibres as well as a carbon resource are briefly reviewed in this section.
The key principle of recycling CFRPs involves the separation of carbon fibres from the resin matrix.
Mechanical processing involves crushing and shredding followed by further grinding and milling down to 10–50 mm of fine particles [9]. Recovered materials/flakes are separated into resin-rich powders and carbon fibres of different lengths still embedded in the resin matrix. Resin-rich powders find applications as fillers in bulk as well as sheet-melding composites [10]. While recovered fibre-rich fractions find reuse in composites [11], their cost and quality are key factors affecting efficient reuse.
Cutting mills were found to produce longer as well as more homogeneous fibre lengths as compared to hammer mills [12]. Direct reforming without grinding has also been used in some cases. Due to significant impairment in mechanical properties and poor bonding between the fibrous fraction and resin, recycled materials are still being used in small concentrations only [13]. Electrodynamic fragmentation has been used to shred carbon fibre-reinforced thermoplastics. Milling dust and chips produced during milling operations have found applications as fillers in the production of thermoplastic granulates with increase in tensile strength and overall rigidity [14]. Degradation in carbon fibre quality is a key issue affecting mechanical processing.
A variety of thermal processes including pyrolysis (heating in the absence of air), fluidised bed and microwave-assisted pyrolysis as well as combustion (heating in the presence of oxygen) have been used for recycling CFRPs [15–17]. Key purpose of these processes is to devolatilize resin to recover carbon fibres; typical temperatures used range between 450 and 700°C depending on the resin used. As high temperatures (>2200°C) are used in the preparation of carbon fibres, relative lower pyrolysis temperatures do not have much effect on basic characteristics of carbon fibres.
Temperatures up to 1550°C are used for recycling of CFRPs for steelmaking applications [18]. Devolatilised resin produces CO2, H2, CH4 gases, an oily fraction as well as char that may deposit on fibre surfaces. Key advantages of pyrolysis (temperature range: 400–1550°C) include retention of mechanical properties, recovery of carbon fibres and the absence of chemicals. Some of the detrimental factors include the deposition of chars on fibre surfaces and hazardous emissions due to thermal degradation of resin [18].
While higher amounts of energy may be consumed during pyrolysis depending on operating temperatures, this process does not cause local area contamination, typically associated with mechanical and physical processing of waste. Deposition of char from degraded resin can be seen clearly in SEM images of CFRPs treated at a range of temperatures (Figure 1). The fibres contaminated by resin char require additional heating in air at 450°C to burn this residual char. However, oxidation can cause strength degradation (up to 50%), shorter fibres and unstructured fibre architecture [20].
In microwave-assisted pyrolysis, direct heating of the material core in inert atmosphere results in fast thermal transfer and energy savings. Lester et al. [17] suspended specimens of carbon fibres and resin in a microwave cavity using quartz sand to suspend the samples and glass wool to limit material loss. Using a bed of silica sand, fluidised bed reactor used hot air for rapid heating and dissociation of resin from the CFRPs matrix [12]. A strength degradation of ~25% was recorded for carbon fibres after heat treatment at 550°C. While this technique can process contaminated as well as end-of-life waste, it is not particularly suitable for recovering carbon fibres.
Solvolysis involves chemical degradation of the resin present in CFRPs with the help of chemical solvents. Water is the most commonly used solvent; organic co-solvents, alkaline as well as acidic catalysts, are also used along with water depending on the nature of the resin involved [21–23]. Low temperatures as well as pressures are used sometimes in conjunction with various solvents; polyester resins require lower temperatures than epoxy resins for degradation and solvolysis. The overall process can therefore be a combination of solvolysis and thermal processes, for example, hydrothermal processes for use of water at higher temperatures.
It is also possible to modify the solvent power and basic characteristics, reactivities and so on by operating under subcritical or supercritical conditions as a function of temperature and pressure [24]. These techniques can recover carbon fibres without much detriment of fibre lengths, distributions and mechanical properties. However, these may not be suitable for contaminated waste or could cause environmental damage when hazardous chemicals are either used or produced as spent byproducts.
Significant research has been carried out on recycling waste CFRPs in attempts to extract carbon fibres, albeit with reduced mechanical and other capabilities, for further reutilization in a variety of lower-grade applications. As recycling rates continue to be very low and landfilling not a viable option due to high costs and/or legislation, the utilisation of waste CFRPs as a carbon resource in steelmaking is being explored [25]. This technique can process waste CFRPs irrespective of the nature and characteristics of fibres, resin and impurities present due to high temperatures (1550°C).
CFRPs typically contain up to 92 wt.% carbon in form of fibre; fibres containing up to 99 wt.% carbon is generally known as graphite fibres. The atomic structure of carbon fibres is similar to graphite and consists of sheets of carbon atoms (graphene sheets) arranged in a regular hexagonal pattern, the key difference being the manner of interlocking between sheets. Precursors used to prepare carbon fibres have a strong influence on atomic-level fibre structure [26].
Carbon fibres derived from polyacrylonitrile (PAN) have a turbostratic structure (random orientation of graphene sheets), whereas carbon fibres derived from the mesophase pitch have a highly ordered graphitic structure. As a potential carbon resource for steelmaking, waste CFRPs have better characteristics as compared to typical carbons, for example, coals, cokes, chars and so on [27].
Carbon dissolution from CFRP powders into molten iron was investigated at 1550°C using sessile drop arrangement [28]. Carbon dissolution investigations showed a rapid carbon pickup reaching ~5.20 wt.% carbon for CFRPs char (K: 22.2 × 10−3 s−1) within 2 min. This level of carbon pickup was similar to that from synthetic graphite and was much higher than typical results from coke, coal chars and natural graphite.
End-of-life waste CFRPs can be used as an alternative source of carbon for carburising purposes in steelmaking. Such sustainable recycling of CFRP materials for the steelmaking industry will be an important pathway towards solving CFRPs' disposal problems such as waste management and landfilling. This research is presently in initial stages. Significant testing and development will be required for commercial-scale applications.
A brief review has been presented on recycling CFRPs, recovering carbon fibres as reusable products, degradation of fibre characteristics after mechanical, thermal and chemical processing of waste. Significant success has been achieved using a wide variety of techniques depending on the nature/type of resin used, fibre precursors, manufacturing source and waste CFRP products being recycled. Commercial industrial scale recycling is not yet economically feasible in most cases. Utilisation of waste CFRPs as an alternate carbon resource in steelmaking is an emerging technology that could reduce the carbon footprint of the steel sector and help redirect this carbonaceous waste from landfills and associated economic and environmental impact.
Cancer is an abnormal growth of cells, which begin to divide without stopping and can form solid tumors. Cancer is a collection of more than 100 different diseases with genetic changes, which can be inherited or be caused by environmental exposure to chemicals, tobacco smoke, or radiation, such as UV rays from the sun.
Cancer is the second leading cause of death in the US and is responsible for approximately 1 out of every 4 deaths. Globally, nearly 1 in 6 deaths is due to cancer. Approximately, 70% of deaths from cancer occur in low- and middle-income countries. There were 14.1 million new cancer cases, 8.2 million cancer deaths, and 32.6 million people living with cancer (within 5 years of diagnosis) in 2012 worldwide, based on World Health Organization (WHO) estimates. A total of 57% (8 million) of new cancer cases, 65% (5.3 million) of cancer deaths, and 48% (15.6 million) of 5-year prevalent cancer cases occurred in less-developed regions [1, 2].
The most common treatments for cancer are surgery, chemotherapy, and radiation therapy, and in many cases, they are used in combination [3]. These treatments can be effective but can cause side effects, such as anemia, appetite loss, fatigue, and alopecia [4].
Plants are an important source of compounds currently used in cancer chemotherapy. The Cucurbitaceae family, also called cucurbits, contains 120 genera with 825 species that are widely distributed in tropical and temperate regions [5], and those with edible fruits were the first cultivated plants in Europe and America. Many species of the Cucurbitaceae family are used as human food [6]. Most of the species in this family are annual vines, and some are lianas, thorny shrubs, or trees. The most important genera of this family are Cucurbita (squash, pumpkin, zucchini), Lagenaria (calabash), Citrullus (watermelon), Cucumis (cucumber, various melons), and Luffa (luffa).
Some cucurbitanes have been isolated from different species of the Cucurbitaceae family. These compounds exhibit an extensive range of biological actions, specifically antidiabetic, anti-inflammatory, cytotoxic, hepatoprotective, cardiovascular, and antiparasitic effects [7].
Cucurbitacins are characteristic compounds in many species of cucurbits. These compounds are tetracyclic triterpenes arising from a rearrangement of the protostane cation and are unsaturated and polyfunctional oxygenated compounds and occur most often as glycosides. They are particularly toxic and bitter chemicals, and their cytotoxicity contributes to their toxicity [8]. Cucurbitanes are found in many plants.
The most significant mechanisms of the apoptotic effects of cucurbitacins are their ability to modify the mitochondrial transmembrane potential and transcriptional activity via nuclear factors or genes and their ability to activate or inhibit pro- or antiapoptotic proteins.
Similar to other plant-derived compounds, cucurbitacins exert toxic effects in different cancer cell lines by inducing apoptosis. The main mechanism of this induction is the ability to modify the mitochondrial transmembrane potential [6].
Therefore, some compounds obtained from Cucurbitaceae could be useful scaffolds for developing new drugs. We consider it necessary to review the main chemicals from this genus with potential anticancer activity.
Cucurbitacins are primarily tetracyclic triterpenoids (Figure 1) that compose a class of biochemical compounds contained in plants of the family Cucurbitaceae, which include the Thai medicinal plants Trichosanthes cucumerina L. and T. kirilowii Maximowicz, the leaves and fruits of the Tunisian plant Ecballium elaterium; the fruits of Cucurbita pepo cv. dayangua; the roots of Cayaponia tayuya (Tayuya), which has long been used in folk medicines from Brazil, Peru, and Colombia; C. racemosa Cong., the roots of Hemsleya amabilis, an ancient Chinese remedy, Cucumis melo L., Momordica balsamina L. (balsam pear), Cucurbita andreana (winter squash), and Citrullus colocynthis (bitter cucumber). Below, the most important cucurbitacins that have shown interesting cytotoxicity and anticancer activity are listed.
Cucurbitacin B (CuB) is an oxygenated tetracyclic triterpenoid compound (1′). The growth-inhibiting effect of CuB was evaluated on MCF-7 and MDA-MB-231 breast cancer cells and B16F10 melanoma cells by the MTT assay. This compound had antiproliferative effects against breast cancer cells in a dose-dependent manner, and the IC50 values for MCF-7 and MDA-MB-231 were 4.12 and 3.68 μM, respectively [9].
CuB potently suppressed the growth of four types of NSCLC cells (H1299, A549, HCC-827, and H661), inhibiting the proliferation of all the cell lines with IC50 values between 0.05 and 0.130 μM. The mean tumor volume at the end of the study in CuB-treated mice was 200 ± 111 mm3, compared to 684 ± 321 mm3 in the control group (average reduction of 70% in tumor volume (p < 0.05). No visible sign of toxicity was observed in CuB-treated mice [10]. CuB could suppress human NSCLC cell growth in vitro through its effects on the PI3Kinase and MAPK pathways, which lead to programmed cell death induction, as well as inhibition of cell migration and cell invasion [11]. Additionally, CuB induces cell cycle arrest in A-549 cells and causes DNA double strand breaks. It also produces DNA damage and G2/M phase arrest; this damage could be due to an increase in reactive oxygen species (ROS) formation [12].
The cytotoxic effect of CuB was tested on HeLa and U2OS cells, and the IC50 values were 12.2 and 17.07 μM, respectively. The inhibition of tubulin polymerization in vitro was observed with an IC50 > 1 mM [13]. CuB from the leaves of Tunisian E. elaterium exhibited an anticancer effect and displayed anti-integrin activity in human glioblastoma U87 cells, with no cytotoxicity observed at concentrations up to 500 nM. CuB affected the adhesion and migration of U87 cells to fibronectin with IC50 values of 86.2 and 84.6 nM, respectively. Time-lapse videomicroscopy showed that CuB significantly reduced U87 cell motility and affected directional persistence. CuB also inhibited cell proliferation with an IC50 value of 70.1 nM, as determined using the crystal violet assay. Moreover, CuB inhibited in vitro human microvascular endothelial cell (HMEC) angiogenesis at concentrations up to 10 nM. Interestingly, this work demonstrated for the first time that this effect was specifically mediated by α5β1 integrins. These findings reveal a novel mechanism of action for cucurbitacin B, which displays potential as a specific anti-integrin drug [14].
C. tayuya (Cucurbitaceae) is a climbing lignified plant with a large tuber that has long been used in folk medicine as an anti-inflammatory, antitumor, and antirheumatic agent. DHCB (2′) was isolated from the roots of C. tayuya and assessed in isogenic colon cancer cell lines HCT116 and Hke-3 by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. This compound induced apoptosis in both cell lines with IC50 values of 9.8 and 4.7 μM, respectively [15].
DHCB inhibited the viability of human cervical cancer cell lines with an IC50 of 40–60 μM, but its cytotoxic effects were less pronounced in normal epithelial fr2 and HerEpiC cells, where the IC50 was 125 μM. The underlying mechanisms were studied, and the results showed that DHCB induced apoptosis in HeLa cells and caused ROS-mediated shifts in the ΔΨm. Additionally, DHCB caused cell cycle arrest in HeLa cells at the G2/M checkpoint. The phosphoinositide 3 kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) cascade may play an important role in cancer tumorigenesis and progression and resistance to chemotherapy. The results indicated that DHCB decreased the expression of important proteins in the PI3K/Akt/mTOR cascade [16].
DHCF (3′) has been isolated from the roots of H. amabilis, an ancient Chinese remedy for bacillary dysentery, gastroenteritis, and cancer. While the toxicity of other cucurbitacins has been explored in several types of cancer, little data exist on the effect of DHCF on human cancers, including prostate cancer (PCa). Human PCa DU145, PC3, and LNCaP cells were treated with graded doses of DHCF in vitro, and the antiproliferative activity of this compound was determined using the MTS assay. DHCF inhibited the proliferation of all three PCa cell lines in a dose-dependent manner. The IC50 values of DHCF in DU145, PC3, and LNCaP cells were 15, 7, and 5 μM, respectively [17].
The inhibition of breast cancer metastasis in mouse models by CuE was reported. To evaluate the effect of CuE on the proliferation and apoptosis of inoculated 4T1 and MDA-MB231 cells in vivo, the expression of proliferating cell nuclear antigen (PCNA) and cleaved caspase-3 was tested by immunohistochemical analysis [18]. CuE targets the dissemination of breast cancer cells from the primary tumor but not the outgrowth of established micrometastases in target organs (lung, liver, between others). CuE exerts no significant effect on tumor cell apoptosis or proliferation in vivo [19].
CuE demonstrated cytotoxic activity against human oral squamous cell carcinoma SAS cells with an IC50 of 3.69 μM and induced the apoptosis of SAS cells after 24 h of treatment, but not MRC-5 or HS68 cells, which showed a dose-dependent reduction. Microscopic examination showed that following exposure to CuE (2.5 μM) for 6–24 h, the cells displayed a remarkable change in their morphology, and CuE induced the death of cancer cells [20].
The inhibitory effect of CuE on the proliferation of Bcap37 and MDA-MB-231 cells was assessed by the MTT assay. Breast cancer cells were treated with various concentrations (0, 0.1, 1, 10, and 100 μM) of CuE or DMSO as a control for 24, 48, and 72 h. The MTT method was then used to determine the number of viable cells. The data indicated that CuE inhibited cell growth in a concentration- and time-dependent manner (ANOVA, p < 0.05). After treatment with 0.1 μM CuE for 24 h, the growth of Bcap37 and MB-231 cells was significantly inhibited. At a CuE concentration of 100 μM, most of the cancer cells detached from the dish [21].
Additionally, CuE was evaluated on the chondrosarcoma SW 1353 cancer cell line, and the IC50 values indicated higher toxicity in this cell line than in the previously test lines (MTT assay). The amount of CuE that induced a mortality of 50% was calculated after 6, 12, and 24 h of treatment, and the results were 13.55, 12.65, and 9.16 μM, respectively [22]. The cytotoxic effect of CuE was tested on HeLa and U2OS cells, and the IC50 values were 6.43 and 15.07 nM, respectively. The inhibition of tubulin polymerization in vitro had an IC50 of 566.91 nM [13].
The effects of CuE from E. elaterium fruit on the expression of the BAX, caspase-3, LC3, and VEGF and c-MYC genes in the AGS cell line were investigated. The sub-G1 accumulation of AGS cells treated with CuE was increased compared to that of untreated cells. Moreover, the treatment of AGS cells with CuE-induced cell death. Additionally, the effects of CuE on the mRNA expression levels of the LC3, VEGF, BAX, caspase-3, and c-MYC genes were evaluated using qRT-PCR. LC3 mRNA levels were increased approximately 20-fold after treatment with CuE at a concentration of 0.1 μg/mL for 24 h. However, BAX, caspase-3, and c-MYC mRNA levels at these concentrations were not changed by the treatment [23, 24].
One additional cucurbitacin was discovered in the roots of C. tayuya and was identified as cucurbitacin R (CCR) (5′). This compound was experimentally assessed in isogenic colon cancer cell lines HCT116 and Hke-3 by the MTT assay and induced the apoptosis of both HCT116 and Hke-3 cells with IC50 values 37 and 27 μM, respectively [15].
CuI, also known as elatericin B or JSI 124, has been isolated from different plants, such as M. balsamina L. (balsam pear), C. tayuya (tayuya), Cucurbita andreana (winter squash), and C. colocynthis (bitter cucumber). This compound was tested in isogenic colon cancer cell lines HCT116 and Hke-3 and was found to induce apoptosis in both lines, with IC50 values of 0.29 and 0.09 μM, respectively [15].
The cytotoxicity IC50 values of CuI in SW 1353 cells after 6, 12, and 24 h of treatment were 7.93, 8.31, and 5.06 μM, respectively [22]. The cytotoxic activity of CuI against SW-480 human colon cancer cells was tested. In this case, CuI diminished cell proliferation in a concentration-dependent manner and increased apoptosis, enhancing cycle arrest at the G2/M phase [25].
The cytotoxicity of CuI was tested in HeLa and U2OS cells, and the IC50 values were 44.77 and 23.47 nM, respectively. The inhibition of tubulin polymerization in vitro had an IC50 > 1 mM [13]. The effects of CuI purified from E. elaterium fruit on the expression of the BAX, caspase-3, LC3, and VEGF and c-MYC genes in the AGS cell line were investigated. The sub-G1 accumulation of AGS cells treated with CuI was increased compared to that of untreated cells. Moreover, treatment of AGS cells with CuI-induced cell death. Additionally, the effects of CuI on the mRNA expression levels of the LC3, VEGF, BAX, caspase-3, and c-MYC genes were evaluated using qRT-PCR. After treatment, at a concentration of 0.5 μg/mL for 24 h, LC3 mRNA levels were increased approximately 25-fold, and VEGF mRNA levels were increased approximately 4.4-fold. However, BAX, caspase-3, and c-MYC mRNA levels were not considerably changed after treatment with CuI [23, 24].
CuD was evaluated in the chondrosarcoma SW 1353 cancer cell line. Its IC50 values against SW 1353 cells after 6, 12, and 24 h of treatment were 16.48, 13.03, and 13.14 μM, respectively [22].
The effects of CuD purified from E. elaterium fruit on the expression of the BAX, caspase-3, LC3, VEGF, and c-MYC genes in the AGS cell line were investigated. The sub-G1 accumulation of AGS cells treated with CuD was increased compared to that of untreated cells. Moreover, the treatment of AGS cells with CuD induced cell death. Additionally, the effects of cucurbitacin D on the mRNA expression levels of the LC3, VEGF, BAX, caspase-3, and c-MYC genes were evaluated using qRT-PCR. LC3 mRNA levels were increased approximately 23-fold after treatment with CuD at a concentration of 0.3 μg/mL for 24 h. However, the BAX, caspase-3, and c-MYC mRNA levels were not considerably changed after treatment. Regarding the effects of CuD and CuE on LC3 mRNA expression, CuD's effect was significantly greater than that of CuE [23].
The antiproliferative effects of Cucurbitacin A (CuA) on A-549 cells were determined by using the MTT assay. This compound exhibited a potent cytotoxic effect on A-549 cells. The assay was carried out at different concentrations of CuA (0, 10, 20, 40, 100, 150, and 200 μM) with incubation for 24 and 48 h. CuA showed inhibitory effects on cell proliferation in a dose- and time-dependent manner. However, the effect of the incubation time was more pronounced at higher doses of the compound. CuA also induced morphological changes in these cells, featuring chromatin condensation, cell shrinkage, and apoptotic body formation. G2/M phase cell cycle collapse was also induced by CuA along with inhibition of the expression levels of m-TOR/PI3K/Akt proteins [26].
This compound is a cucurbitacin isolated from Cayaponia racemosa Cong. The anticancer activity of RPO was evaluated with in vitro and in vivo models. Cucurbitacin (9′) reduced the number of viable HL-60 leukemia cells; however, there was no change in the number of nonviable cells at 5 μg/mL. This compound had no effect on normal proliferating lymphocytes at the concentrations tested (IC50 > 25 μg/mL). Morphological analysis of RPO-treated cells showed typical apoptotic features, such as heavy deposition of granules in the cytoplasm (eosinophilia), DNA fragmentation and irregularities in the plasma membrane, and intense vacuolization and disruption of the plasma membrane. Acridine orange/ethidium bromide staining confirmed these findings, revealing an increased number of apoptotic cells. In the sarcoma 180 tumor model, compound (9′) showed 52 or 62% antitumor activity when administered alone (25 mg/kg/day) or in association with the chemotherapeutic agent 5-FU (10 + 10 mg/kg/day), respectively. Moreover, treatment with compound (9′) either alone or in combination with 5-FU caused an increase in spleen weight and morphological alterations related to immunostimulatory properties [27].
Phytochemical investigation of the fruits of Cucurbita pepo cv. dayangua led to the isolation of cucurbitaglycosides A (10′) and B (11′). This was the first report of cucurbitane triterpenoids with a purine unit. Cucurbitaglycosides A and B showed cytotoxic activity against the human epithelial carcinoma cell line HeLa with IC50 values of 17.2 and 28.4 μg/mL, respectively [28].
Three cucurbitane triterpenoids were isolated from H. amabilis, and the main compound was Hemslecin A (HA). This compound showed significant cytotoxic activity against HeLa cells with an IC50 value of 0.389 μM. Additionally, 7β-hydroxycucurbitacin F-25-O-acetate (13′) and 2β,3β,20(S),26,27-pentahydroxy-16α,23(S)-epoxycucurbita-5,24-dien-11-one (14′) (Figure 2) were isolated and showed less cytotoxic activity (IC50 values of 12.3 and 387 μM, respectively) than HA [29].
Several new cucurbitane-type triterpene glycosides (Figures 3 and 4) have been isolated from the fruit pulp of Momordica charantia L., and their cytotoxic activity has been evaluated.
Two new cucurbitane-type triterpene glycosides, charantagenins D (15′) and E (16′), and one new sterol, 7-oxo-stigmasta-5, 25-diene-3-O-β-D-glucopyranoside (17′), were isolated from the fruit of M. charantia L. together with another six known compounds (18′–23′). The cytotoxic activities of the major isolated compounds were evaluated against the lung cancer cell line A549, glioblastoma cell line U87, and hepatoma carcinoma cell line Hep3B using in vitro MTT assays. Two new cucurbitane-type triterpenes, 25-methoxycucurbita-5,23(E)-diene-3β,19-diol (24′) and 7β-ethoxy-3β-hydroxy-25-methoxycucurbita-5,23(E)-dien-19-al (25′), together with three known cucurbitane-type triterpenes, 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (26′), (23E)-3β-hydroxy-7β,25-dimethoxycucurbita-5,23-dien-19-al (27′), and 3β-hydroxy-25-methoxycucurbita-6,23(E)-dien-19,5β-olide (28′), were isolated from the fruit pulp of M. charantia. Their cytotoxic activity was evaluated against human hepatoma SK Hep-1 cells with etoposide as a positive control (IC50 = 3.7 μM). The results are shown in Table 1 [19, 30].
|Cancer cell line
|IC50 values (μM)
|A549 lung cancer cell line
|15′ = 1.07
|16′ = 3.82
|17′, 22′, 23′ = >100
|18′ = 4.46
|19′ = 4.89
|20′ = 5.32
|21′ = 15.10
|U87 glioblastoma cell line
|15′ = 1.08
|16′ = 67.32
|17′,18′,22′,23′ = >100
|19′ = 0.60
|20′ = 0.19
|21′ = 8.65
|Hep3B hepatoma carcinoma cell line
|15′ = 14.01
|16′–19′,21′–23′ = >100
|20′ = 19.30
|SKHep1 human hepatoma cell line
|24′ = 33.1
|25′ = 24.3
|26′ = >50
|27′ = >13
|28′ = 38.7
Several new cucurbitane triterpenoids were isolated from the stems and leaves of M. charantia and tested against five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480). Only momordicin VII (29′) was slightly active, with IC50 values of 16.2, 20.3, 20.5, 16.9, and 14.3 μM, respectively [31].
Multiflorane-type triterpenes (Figure 5), a new class of cucurbitacins, were isolated from seeds of Cucurbita maxima, along with three known compounds from Benincasa hispida (Thunb.) Cogn., fruits that are widely consumed in China and tropical countries, and these compounds were found to exhibit interesting cytotoxicity activity.
Three new multiflorane-type triterpenes, 7α-methoxymultiflor-8-ene-3α,29-diol-3-acetate-29-benzoate (30′), 7-oxomultiflor-8-ene-3α,29-diol-3-acetate-29-benzoate (31′), and multiflora-7,9(11)-diene-3α,29-diol-3-p-hydroxybenzoate-29-benzoate (32′), were isolated from seeds of C. maxima, along with three known compounds. These compounds exhibited cytotoxicity against HL-60 and P388 cells. Compound (30′) did not show significant cytotoxic activity, with an IC50 > 100 μM in both lines, but compounds 31 and 32 showed cytotoxic activity against HL-60, with IC50 values of 7.1 and 7.1 μM, respectively. The IC50 values for P388 were 55.9 and 92.6 μM, respectively [32].
Analysis of Benincasa hispida (Thunb.) Cogn. fruits yielded three new triterpenoids, 3α,29-O-di-trans-cinnamoyl-D:C-friedooleana-7,9(11)-diene (33′), oleanolic acid 28-O-β-D-xylopyranosyl-[β-D-xylopyranosyl-(1→4)]-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside (34′), and oleanolic acid 28-O-β-D-glucopyranosyl-(1→3)-β-D-xylopyranosyl-[β-D-xylopyranosyl-(1→4)]-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside (35′). The cytotoxic activities of compounds (33′−35′) were assessed by the MTT assay. These compounds showed no significant cytotoxic activity against HeLa human cervical, HL-60 human hepatoma, and SMMC-7721 human hepatoma cell lines [33].
Cyclic bisdesmosides, new compounds analogous to cucurbitacins, share the tetracyclic triterpenoid core but contain carbohydrates to form a bicycle (Figure 6). These compounds were isolated from Actinostemma lobatum MAXIM and Bolbostemma paniculatum (Maxim) Franquet.
Two new cyclic bisdesmosides elucidated as lobatoside L (36′) and lobatoside M (37′) and four known cyclic bisdesmosides (38′–41′) were isolated from A. lobatum Maxim. The inhibitory effects of these six compounds on human cancer cell growth (including the esophageal squamous carcinoma cell line ECA109, lung cancer cell line A549, and gastric cancer cell line MGC-803) were determined using the MTT assay. The six compounds exhibited cytotoxicity against all the cell lines tested, and compounds (36′, 38′, and 40′) showed significant activity in a dose-dependent manner against all the cell lines. The IC50 values for compounds (36′ and 40′) against ECA-109 cells were 8.25 and 3.71 μM, respectively. The rest of the results are shown in Table 2 [34].
|Cancer cell lines
|IC50 values (μM)
|Esophageal squamous carcinoma cell line ECA-109
|36′ = 8.25
|37′ = 74.14
|38′ = 22.37
|39′ = 71.97
|40′ = 3.71
|41′ = 83.53
|Lung cancer cell line A549
|36′ = 26.52
|37′ = 69.28
|38′ = 27.27
|39′ = 77.79
|40′ = 35.12
|41′ = 77.02
|Gastric cancer cell line MGC-803
|36′ = 35.33
|37′ = 84.71
|38′ = 36.85
|39′ = 90.49
|40′ = 35.21
|41′ = 96.55
Tubeimoside I (42′) isolated from B. paniculatum (Maxim) Franquet exhibited cytotoxic activity against HepG2 human cancer cells. The IC50 values at different times of exposure (24, 48, and 72 h) were 15.5, 11.7, and 9.2 μM, respectively. This compound induced shrinkage, nuclear condensation, fragmentation, and cell cycle arrest in phase G2/M. The inhibition of growth in this case is mediated by a cascade of apoptosis [35].
The gypenosides (Figure 7) were isolated from Gynostemma pentaphyllum and from the aerial parts of G. pentaphyllum.
Gypenoside L (43′) and gynogenin (44′), 20(S)-dammar-24-en-2a,3b,12b,20-tetrol, were isolated from G. pentaphyllum and tested against A-549 lung carcinoma cells. The IC50 values were 34.94 and 12.54 μg/mL, respectively [36]. Some gypenosides were isolated from the aerial parts of C. pentaphyllum (45′–51′), and their structures were elucidated with spectroscopic and chemical methods. Their cytotoxic activity was determined against different human cancer cell lines, A549, HT-29, MCF-7, and SK-OV-3. All the compounds showed low activity, with IC50 values between 62.8 and 19.6 μM [37].
In addition to the cucurbitacins, other substances isolated from the Cucurbitaceae family have been identified, including proteins isolated from the sarcocarp of Cucurbita moschata (pumpkin) and from the root of T. kirilowii Maxim (Cucurbitaceae). Additionally, the protein from the root of T. kirilowii Maxim has been demonstrated to possess important cytotoxicity activity.
A novel type-1 ribosome-inactivating protein (RIP) designated cucurmosin was isolated from the sarcocarp of Cucurbita moschata (pumpkin). Its structure contains two domains: a large N-terminal domain composed of seven α-helices and eight β-strands and a smaller C-terminal domain consisting of three α-helices and two β-strands (Figure 8).
Cucurmosin was tested for its cytotoxicity against human leukemia cells (K562), murine melanoma cells (B16), lung adenocarcinoma cancer cells (A549), and peripheral blood lymphocytes using the standard MTT assay. The IC50 values of cucurmosin were 88.1, 63.4, and 359.3 nM in human leukemia cells (K562), murine melanoma cells (B16), and lung adenocarcinoma cancer cells (A549), respectively, while its IC50 in normal cells (peripheral blood lymphocytes) was higher than 1.4 μM [38].
Trichosanthin was isolated from the roots of T. kirilowii Maxim and has been used in traditional Chinese medicine. This compound was tested against HepG-2 and WRL 68 cells, and the IC50 values obtained were 10.38 and 15.45 μmol/L, respectively [39].
Tianhua, an extract of T. kirilowii, was analyzed to determine its mechanism of action against lung cancer cells (A549) using the MTS assay. This compound induced apoptosis via an anti-telomerase effect but had no effect on stimulating peripheral lymphocytes to produce interferon (IFN)-γ; tianhua inhibited the metastatic ability of cells and inhibited the growth of cancer cells in vivo [40].
The aim of this review is to present 51 cucurbitacin compounds and two compounds with different structures isolated from Cucurbitaceae plants, their chemical structures, their biological activities, and the mechanisms by which these compounds reduce the proliferation of cancer cells.
The authors declare that there is note conflict of interest.
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B.C. Securities Commission panel refuses to lift preservation order over retirement accounts of convicted fraudster
Don't assume that you will have easy access to retirement savings if you commit securities offences in British Columbia.
That's one take-away from a recent decision by a three-member B.C. Securities Commission panel.
It dismissed an application from a convicted fraudster, Earle Douglas Pasquill, who had filed an application seeking to revoke a commission preservation order.
It concerned his two life-income accounts at a wealth-management firm.
Pasquill alleged that he personally benefited by only $400,000 through his actions with the Freedom Investment Club Group, even though he was involved in a $21.7-million fraud.
That didn't persuade the commission to vary the preservation order.
"In dismissing this suggestion, we note that the Applicant has not paid any part of even the $400,000 from which he says he personally benefitted," commissioners George C. Glover, Jr., Deborah Armour, and Marion Shaw ruled. "Further, through the fraudulent acts of the Applicant and others, members of the investing public lost $21.7 million."
In 2014, an earlier commission panel concluded that Pasquill, a business partner, and several of their companies had raised this sum from 698 investors. And the scamsters did this without divulging issues related to their FIC Group's financial condition.
In addition, the earlier panel found that Pasquill, his partner, and associated companies raised another $9.9 million from 331 investors for investments in foreclosure properties. However, the commission ruled that they had actually siphoned away most of the money to provide unsecured loans to FIC Group companies.
Back in 2015, the respondents, including Pasquill, were ordered to pay back the commission $21.7 million. In addition, they were assessed a $15-million administrative penalty.
Legal arguments in the recent application came down to whether the commission had authority to impose a preservation order on a convicted fraudster's retirement savings.
"The Applicant argued that because of the special status of registered plans containing assets derived from pensions, the legislature cannot have intended that such plans, including the LIF Accounts, would be subject to enforcement processes taken under the Act," the commissioners stated in their recent ruling. "We see no basis to make that distinction."
The commissioners also rejected the applicant's argument that the tribunal cannot legally make "collateral orders" to implement an earlier decision.
That's because the commissioners concluded that section 164.04(2)(c) of the Securities Act allows a preservation order to be issued in a case like this.
In the meantime, Pasquill's wife, retired teacher Vicki Pasquill, and her company, Vicker Holdings Ltd., filed a lawsuit in B.C. Supreme Court in 2018 against the commission.
According to a Vancouver Sun story at the time, she alleged abuse of process after the commission had filed legal action to get access to seven properties that she owns.
Vicki Pasquill and Vicker Holdings filed a second lawsuit against the commission in 2019. On July 27, 2020, the most recent chambers application was adjourned.


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A Historical Discourse, Delivered by Request, Before the Citizens of Farmington, November 4, 1840: In Commemoration of the Original Settlement of the Ancient Town, in 1640
L. Skinner, 1841 - 99 pages
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Page 14 - ... if you will be satisfied to enjoy such civil and lawful liberties, such as Christ allows you, then will you quietly and cheerfully submit unto that authority which is set over you, in all the administrations of it, for your good.
Page 15 - ... and obedience in their lawful administrations, not beholding in them the ordinariness of their persons, but God's ordinance for your good ; not being like the foolish multitude, who more honor the gay coat, than either the virtuous mind of the man, or the glorious ordinance of the Lord...
Page 14 - The great questions that have troubled the country are about the authority of the magistrates and the liberty of the people. It is yourselves who have called us to this office, and, being called by you, we have our authority from God...
Page 51 - What Constitutes a State? WHAT constitutes a State? Not high-raised battlement or labored mound, Thick wall or moated gate � Not cities proud with spires and turrets crowned � Not bays and broad-armed ports, Where, laughing at the storm, rich navies ride � Not starred and spangled courts, Where low-browed baseness wafts perfume to pride. No; men, high-minded men...
Page 14 - There is a twofold liberty, natural (I mean as our nature is now corrupt) and civil or federal. The first is common to man with beasts and other creatures. By this, man, as he stands in relation to man simply, hath liberty to do what he lists; it is a liberty to evil as well as to good. This liberty is incompatible and inconsistent with authority, and cannot endure the least restraint...
Page 12 - ... it being as unnatural for a right New England man to live without an able ministry as for a smith to work his iron without a fire.
Page 81 - She is not afraid of the snow for her household: for all her household are clothed with scarlet.
Page 15 - Lastly, whereas you are to become a body politic, using amongst yourselves civil government, and are not furnished with any persons of special eminency above the rest to be chosen by you into office of government...
Page 87 - With the testimony of a good conscience, in simplicity and godly sincerity, not with fleshly wisdom, but by the grace of God, he had his conversation in the world.
Page 7 - If this be all your party hath to say, I will make them conform themselves, or else I will harry them out of the land, or else do worse.


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I love being apart of the #PlayLikeHasbro team because I get awesome perks like trying out some of their newest and best toys! If you are still shopping or looking for great ideas for the little ones in your life, here are some of my suggestions in the Ultimate Hasbro Holiday Toy Guide. The Doh Vinci Spotlight Spin Studio is what my artistic 10 year old daughter is most excited about. We became familiar with Doh Vinco last year when we went to Florida for Family Forward conference. Doh Vinci … [Read more...]
Super Hero Assemble App Tutorial
This shop has been compensated by Collective Bias, Inc. and its advertiser. All opinions are mine alone. #AvengersUnite #CollectiveBias I've always been a big super hero fan. When I was younger I would read comics and watch all the super hero cartoons. As I grew up I always keep myself in the super hero "loop". I have loved all the movies and the super hero universe that Marvel has created and continues to expand. I look forward to these movies so much! Whenever there is a super hero app … [Read more...]
Simple DIY Winter Soldier Costume
Here is a simple Do It Yourself Winter Soldier costume. All you need is: black long sleeve shirt grey long sleeve shirt black glove black pants red heat transfer material thick black marker Optional items: goggles face mask shoulder straps Making the Shirt The shirt is the only thing that you need to make for this costume. All you need to do is remove a sleeve from the black shirt and add lines and a red star to the grey shirt. The Complete Costume Put … [Read more...]
Marvel's AVENGERS: AGE OF ULTRON Poster & Trailer
I have been out of the country for the past week without internet access. Yesterday when we finally got back in the US and I checked my email I had this poster and teaser trailer in my inbox. I informed my husband and he about had a heart attack. We couldn't watch it right then because we were trying to get on a flight, but as soon as he had a minute he tracked down the trailer. You don't have to track it down, it's right here: Marvel's AVENGERS: AGE OF ULTRON will hit theaters … [Read more...]
First Look at Marvel's Ant Man
My husband is a HUGE Marvel fan so the other day when I received this photo and little bit of information about Ant Man he was tripping all over himself to get to the computer screen to see this. All the while I'm quietly (or maybe not so quietly) thinking why did they make a super hero called Ant Man? What heroic qualities do ants have? I guess I have a lot to learn! lol For everyone interested in the details here is the press release featuring actors, locations and such: MARVEL STUDIOS … [Read more...]
Captain America: The Winter Soldier Directed by the Russo Brothers
Disclosure: Disney provided me an all expense paid trip to Los Angeles to help promote Muppets Most Wanted, Captain America and other projects. All experiences and opinions are my own. Yours may differ. It was really interesting to talk about the movie from the directors point of view. Their job is so unique and different from the actors that they really did offer a different perspective on the film. Read their interview plus check out these amazing behind the scenes photos I have to … [Read more...]
Teaser Trailer for THOR: The Dark World
Get ready, here is a teaser trailer for the new THOR movie. Hottie with a hammer coming through! :) … [Read more...]


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TV Series | TV-PG | Action, Adventure, Comedy
Using the power of the Imagin and the Rider Pass, Ryotaro Nogami is able to travel to different times through the DenLiner. By traveling through time, he transforms into Kamen Rider Den-O, ... See full summary »
Korean, Japanese
Looking for something new to watch in December? Here are some picks to fill your Watchlist.


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Four Boys in the White House: The Children of James and Ellen White ePub download
by Paul B. Ricchiuti
- Author: Paul B. Ricchiuti
- ePub: 1876 kb | FB2: 1346 kb
- Category: Protestantism
- Publisher: Stanborough Press Ltd (April 1, 2008)
- Pages: 104
- Rating: 4.4/5
- Votes: 332
- Format: docx mobi lrf doc
ISBN13:9781904685500. Release Date:March 2008.
Fear: Trump in the White House is a non-fiction book by American journalist Bob Woodward about the presidency of Donald Trump. The book was released on September 11, 2018. Woodward based the book on hundreds of hours of interviews with members of the Trump administration. The book's publisher Simon & Schuster announced that it had sold . million copies (across all formats) in the first week of its release, making it the fastest selling opener in the company's history.
The White House Building. Less than fifty years after the Roosevelt renovation, the White House was showing signs of serious structural weakness. James Hoban was appointed to rebuild the house, and President James Monroe moved into the building in 1817. During Monroe's administration, the South Portico was constructed in 1824, and Andrew Jackson oversaw the addition of the North Portico in 1829. President Harry S. Truman began a renovation of the building in which everything but the outer walls were dismantled.
Details (if other): Cancel. Thanks for telling us about the problem. Ellen White: Friend of Angels: Stories from Her Amazing Adventures, Travels, and Relationships. by. Paul B. Ricchiuti
Ellen White walked into human history at the right time with the right message-a message for a world of many . Ricchiuti is an award-winning author of books-most of them for children.
Ellen White walked into human history at the right time with the right message-a message for a world of many changes with men and women trying newfound freedoms. But as the 1800s wore on, people failed to identify with her as a living flesh-and-blood person. He is the recipient of the Certificate of Merit from International Authors and Writers Who's Who-Cambridge, England, 1986, and the Distinguished Leadership Award from the American Biographical Institute for Outstanding Service to the Literary Profession.
In Wyoming, she visited national parks and spoke with children about the value of getting out in nature!
In Wyoming, she visited national parks and spoke with children about the value of getting out in nature! The White House. 12 hrs ·. We have the best military and the best intelligence anywhere in the world. If Americans are threatened, we are prepared to respond. It looks like you may be having problems playing this video. If so, please try restarting your browser. President Trump: The best military anywhere in the world. Posted by The White House.
and one of those white flabby faces that looked exactly as though it had been . The next moment, James was running back towards the house as fast as he could go. He would do it all.
and one of those white flabby faces that looked exactly as though it had been boiled. She was like a great white soggy overboiled cabbage. Aunt Spiker, on the other hand, was lean and tall and bony, and she wore steel-rimmed spectacles that fixed on to the end of her nose with a clip. And as he worked, James began thinking about all the other children in the world and what they might be doing at this moment. Some would be riding tricycles in their gardens. Some would be walking in cool woods and picking bunches of wild flowers.
The children's life of the bees by Maurice Maeterlinck -Thomas Jefferson for Kids: His Life and Times with 21 Activities by. .
The children's life of the bees by Maurice Maeterlinck -Thomas Jefferson for Kids: His Life and Times with 21 Activities by Brandon Marie Miller -Brian P. Cleary, Brian Gable, "Quirky, Jerky, Extra Perky: More About Adjectives" -Fault Lines & Tectonic Plates: Discover What Happens When the Earth's Crust Moves With 25 Projects (Build It Yourself) by Kathleen M. Reilly -Social Skills fo.
Red House Children's Book Award. The Federation of Children's Book Groups Children's Book Award is a set of annual literary prizes for children's books published in the . during the preceding calendar year. It recognises one "Overall" winner and one book in each of three categories: Books for Younger Children, Books for Younger Readers, and Books for Older Readers.


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When the cold wind hits you in the morning you better be afraid
Do you have a over dramatic partner? This could happen to you
It's hard being tough in 2019
South African prankster Leon Schuster sets up and plays the fool with a new intake of traffic police.
Funny South African student Mo Ngcobondwane interviewed on ETV
Brasse Funny Carp vs Laeeqah Ryklief, Cape Towns Cyber Bully kak funny music video! Warning lots of swearing HA HA HA. Social media has erupted following the release of a video showcasing a C...
Frankie du Toit and the guys from Bad Peter did their own Afrikaans version of the Adele song! They were jealous of Rian ...


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J.R. Miller
: May 29. Needless Doubts
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"Calling two of them, John sent them to the Lord to ask: Are you the one who was to come — or should we expect someone else?" Luke 7:18-19
John did not doubt the Messiahship of Jesus that day beside the Jordan, when from the cloven heavens, the radiant Dove descended upon Him and the Father's voice was heard in loving approval. Nor did He doubt in any of the bright days that followed. It was only when it grew dark for John himself, that he doubted.
That is just the way yet with many people. When everything is bright and sunny — they think they have surely found Christ, and they believe He is their friend, and their hearts are full of joy. But when troubles come and things begin to go against them — then they wonder whether, after all, they have really found the Savior. They begin to question their own experiences. "Am I really a Christian? Was that really conversion, when I thought I was saved? or is there some other experience that I must yet have?" Christ does not do just the things they thought He would do for them. Their religion does not support them as firmly as they supposed it would. If they are indeed Christians — then why does Christ let them suffer so much and not come to relieve them? So they sink away down into the Slough of Despond, some times losing all hope.
See how unnecessary was John's doubt. Jesus was indeed the Messiah. John's active work was done, and he was now to glorify God by suffering, and soon by martyrdom.
Just as needless, is all anxiety of Christian people in their times of darkness. Of course we must have some earthly trials. Christ does not carry us to Heaven on flowery beds of ease. We must expect to bear the cross for many a mile. The true way for us, is never to doubt Jesus. Suppose there are clouds — the sun still shines behind them undimmed. Suppose we have failures, trials, and disappointments — Jesus is the same loving friend as when there was not a speck of trouble for us in all the world.
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