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β-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation

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Abstract

Both PI3K/AKT/mTOR/S6K1 and mitogen activated protein kinase (MAPK) signaling cascades play an important role in cell proliferation, survival, angiogenesis, and metastasis of tumor cells. In the present report, we investigated the effects of β-caryophyllene oxide (CPO), a sesquiterpene isolated from essential oils of medicinal plants such as guava (Psidium guajava), oregano (Origanum vulgare L.), cinnamon (Cinnamomum spp.) clove (Eugenia caryophyllata), and black pepper (Piper nigrum L.) on the PI3K/AKT/mTOR/S6K1 and MAPK activation pathways in human prostate and breast cancer cells. We found that CPO not only inhibited the constitutive activation of PI3K/AKT/mTOR/S6K1 signaling cascade; but also caused the activation of ERK, JNK, and p38 MAPK in tumor cells. CPO induced increased reactive oxygen species (ROS) generation from mitochondria, which is associated with the induction of apoptosis as characterized by positive Annexin V binding and TUNEL staining, loss of mitochondrial membrane potential, release of cytochrome c, activation of caspase-3, and cleavage of PARP. Inhibition of ROS generation by N-acetylcysteine (NAC) significantly prevented CPO-induced apoptosis. Subsequently, CPO also down-regulated the expression of various downstream gene products that mediate cell proliferation (cyclin D1), survival (bcl-2, bcl-xL, survivin, IAP-1, and IAP-2), metastasis (COX-2), angiogenesis (VEGF), and increased the expression of p53 and p21. Interestingly, we also observed that CPO can significantly potentiate the apoptotic effects of various pharmacological PI3K/AKT inhibitors when employed in combination in tumor cells. Overall, these findings suggest that CPO can interfere with multiple signaling cascades involved in tumorigenesis and used as a potential therapeutic candidate for both the prevention and treatment of cancer.

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... Src, JAK1, and JAK2 may be involved in β-caryophyllene-induced STAT3 inactivation. β-caryophyllene suppresses the PI3K/AKT signaling pathway, and therefore acts as a strong anticancer agent [90]. Figure 6. ...
... α-Caryophyllene, β-caryophyllene, and β-caryophyllene oxide are sesquiterpenes from terpenoids naturally isolated from the essential oils of pine species and many other aromatic plants. Caryophyllenes inhibit the proliferation of different types of cancer cells, such as those of liver, breast, lung, and prostate adenocarcinoma [90,115,116]. β-Caryophyllene suppresses STAT3 activation in human breast and prostate carcinoma and in multiple myeloma cell lines via the inactivation of IL-6 [36]. Src, JAK1, and JAK2 may be involved in β-caryophyllene-induced STAT3 inactivation. ...
... Src, JAK1, and JAK2 may be involved in β-caryophyllene-induced STAT3 inactivation. β-caryophyllene suppresses the PI3K/AKT signaling pathway, and therefore acts as a strong anticancer agent [90]. ...
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The incidence of various types of cancer is increasing globally. To reduce the critical side effects of cancer chemotherapy, naturally derived compounds have been considered for cancer treatment. Gymnosperms are a group of plants found worldwide that have traditionally been used for therapeutic applications. Paclitaxel is a commercially available anticancer drug derived from gymnosperms. Other natural compounds with anticancer activities, such as pinostrobin and pinocembrin, are extracted from pine heartwood, and pycnogenol and enzogenol from pine bark. Gymnosperms have great potential for further study for the discovery of new anticancer compounds. This review aims to provide a rational understanding and the latest developments in potential anticancer compounds derived from gymnosperms.
... The expression of the antiapoptotic protein Bcl-2 was concurrently signi cantly (P > 0.001) reduced in CPO-treated cells. In line with earlier research, it has been found that CPO inhibits tumour growth and induces apoptosis in human prostate and breast cancer cells by inhibiting PI3K/AKT/mTOR/S6K1 [30] and in non-small cell lung cancer by affecting miR-659-3p-targeted sphingosine kinase 1 [35]. Additionally, HeLa cells (human cervical adenocarcinoma cells), Hepatocellular cancer cells, gastric cancer cells (SNU-1), and stomach cancer cells (SNU-16) are all cytotoxic when exposed to CPO isolated from Jeju guava (Psidium cattleianum Sabine) leaves [15]. ...
... Thus, the current study also suggests that the anticancer effect of CPO is independent of the increase in oxidative stress that can induce cancer cell death and the intrinsic pathway is not activated by ROS in A549 cells treated with CPO. This is consistent with the suppression of ROS-mediated mitogen-activated protein kinase activation by CPO in lung cancer cells [30], which inhibits cancer progression. ...
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One of the most common cancers that result in death is lung cancer. There is new hope in the fight against lung cancer thanks to the chemopreventive properties of natural dietary substances like β-caryophyllene oxide (CPO), and research is currently being done to test this theory. CPO, a sesquiterpene isolated from medicinal plant essential oils, inhibits carcinogenesis and has been effective in treating many cancers. This study examined how CPO affected proliferation of human lung cancer A549 cells. CPO was found to have an inhibitory concentration (IC50) of 124.1 g/ml. The proliferative markers Ki67 and PCNA were significantly inhibited after cells were treated with CPO at a concentration of 50 g/ml compared to controls. CPO-treated cells expressed more P21, P53, and DNA strand breaks than controls. This was accompanied by a significant cell cycle arrest in the S and G2/M phases. In treated A549 cells, this was also associated with a significant induction of apoptosis, as shown by the upregulation of the expression of caspases 3, 7, and 9, as well as Bax, and the downregulation of Bcl-2. Furthermore, the redox status of treated A549 cells revealed a marked rise in GSH and GPx activity levels and a decline in 4-HNE levels, indicating low oxidative stress following CPO treatment of A549 cells. In conclusion, cell cycle arrest and apoptosis, which are unrelated to oxidative stress, were the mechanisms by which CPO reduced cancer lung cell growth. This finding might be a potential therapeutic target for the treatment of lung cancer.
... Together, these two properties may also enhance cellular immunity by activation of detoxification systems and DNA repair [2]. Several studies have also identified diverse pathways of anti-proliferative mechanisms of key oil components in cancer cell lines [91][92][93][94]. The most common mechanism is the induction of apoptosis leading to cytoskeletal alterations, plasma membrane damage, mitochondrial dysfunction, DNA fragmentation, caspase-3 activation, and cleavage of pro-survival proteins [91][92][93][94]. ...
... Several studies have also identified diverse pathways of anti-proliferative mechanisms of key oil components in cancer cell lines [91][92][93][94]. The most common mechanism is the induction of apoptosis leading to cytoskeletal alterations, plasma membrane damage, mitochondrial dysfunction, DNA fragmentation, caspase-3 activation, and cleavage of pro-survival proteins [91][92][93][94]. Although these mechanisms are not entirely understood, they seem to be effective against glioblastoma, melanoma, leukemia, bone, breast, lung, ovary, pancreas, and prostate cancers [95]. ...
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Taraxacum officinale (TO) has been historically used for medicinal purposes due to its biological activity against specific disorders. To investigate the antioxidant and the antiproliferative potential of TO essential oil in vitro and in vivo, the chemical composition of the essential oil was analyzed by GC-MS. The in vivo antioxidant capacity was assessed on liver and kidney homogenate samples from mice subjected to acetaminophen-induced oxidative stress and treated with TO essential oil (600 and 12,000 mg/kg BW) for 14 days. The in vitro scavenging activity was assayed using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and the reducing power methods. The cytotoxic effects against the HeLa cancer cell line were analyzed. The GC-MS analysis showed the presence of 34 compounds, 8 of which were identified as major constituents. The TO essential oil protected mice’s liver and kidneys from acetaminophen-induced oxidative stress by enhancing antioxidant enzymes (catalase, superoxide dismutase, and glutathione) and lowering malondialdehyde levels. In vitro, the TO essential oil demonstrated low scavenging activity against DPPH (IC50 = 2.00 ± 0.05 mg/mL) and modest reducing power (EC50 = 0.963 ± 0.006 mg/mL). The growth of the HeLa cells was also reduced by the TO essential oil with an inhibition rate of 83.58% at 95 µg/mL. Current results reveal significant antioxidant and antiproliferative effects in a dose-dependent manner and suggest that Taraxacum officinale essential oil could be useful in formulations for cancer therapy.
... Moreover, study results of both in vitro and in vivo models indicates that curcumin interferes between attachment of virus to host cells, resulting in interruption of virus entry, replication and budding. In addition, animal models exhibited that curcumin extensively prevented the pulmonary dysfunction and minimized organ damage (Aggarwal et al., 2007;Lee et al. 2011;Lee 2015;Patel et al., 2018;Gibson et al. 2020;Tzotzos et al. 2020 andMemarzia et al. 2021). ...
... It is known to help relieve anxiety and pain, reduce cholesterol, prevent osteoporosis, and treat seizures. Reports also showed that caryophyllene suppressed PC-3-Prostate cancer cell and MCF-7-breast cancer cell proliferation in a dose dependant manner (K.R. Park et al., 2011). ...
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Jour Pl Sci Res 38 (1) 2022 Climate Change and Health and Ayush: Curcuma and COVID-19 Heat waves hit both poles at once. Planet earth is warming and climate change is affecting. “Temperature records were smashed in Antarctica last week: one weather station recorded temperatures that were 40! above normal. At the same time, it is 30! warmer than average at the North Pole. “They are opposite seasons. You don’t see the North and the South [Poles] both melting at the same time,” says ice scientist Walt Meier. (https://apnews.com/article/climate-science�colorado-arctic-antarctica-eda 9ea 8704108bdab2480 fa2cd4b6e34?utm_source= Nature+Briefing&utm_ campaign=9faf4287e9-briefing-dy-20220321&utm_ medium=email&utm_term=0_c9dfd39373-9faf4287e 9-45318994). “Not a good sign when you see that sort of thing happen,” said University of Wisconsin meteorologist Matthew Lazzara. Although both Lazzara and Meier said what happened in Antarctica is probably just a random weather event and not a sign of climate change, but if it happens again or repeatedly then it might be something to worry about and part of global warming, they said. In my own experience as student in 1965-1967 period, Jaipur the pink city (the capital and largest city of the Indian state of Rajasthan) was so cool that its maximum temperature in summer was about 37o C even in May and June. The highest temperature was 42o C and within two or three days rain splashes will come. Jaipur was surrounded by hills and almost on all sides and hills were lush green after the rain. Ramgarh dam as source of water for entire city, used to overflow in rainy season and Jaipur had a population of around a lac or so in 1947. A single bus of Kamal Co used to run between stations (some 6 km from city) and walled city during early days of freedom. However, Jaipur and Udaipur (another city in the state of Rajasthan, India) or for that matter any city of the world is facing climate change but there is no concern in the present generation of politicians, scientists, medical and health practitioners as if nothing is happening. UN bodies are more of an ornamental structures. Any solutions to global warming mitigation are not spread or accepted even by those nations who will be most affected by climate change the poorest of the poor. CO26 is just another meeting and IPCC reports are just a number. Jaipur temperatures or for that matter all temperature across India are reaching 6 degrees higher than normal. It is almost 40 to 42o C in most cities of Rajasthan. The Journal of Plant Science Research is doing its part in understanding the phenomenon and providing solutions. Can you believe idea of plant-based vaccine that too from a plant commonly use as vegetable in India? Yes, this week it’s official that Medicago’s homegrown, plant-based COVID-19 vaccine has been approved by Health Canada (https://www.cbc.ca/ news/health/medicago-s-homegrown-plant-based�covid-19-vaccine-approved-by-health-canada�1.6362745?utm_source=Nature+Briefing&utm_campaign =8f 4263cf0e-briefing-dy-20220315&utm_ medium =email&utm_term=0_c9dfd3). The shots use Medicago’s plant-derived, virus-like particles — which resemble the coronavirus behind COVID-19 but don’t contain its genetic material — and also contain an adjuvant from GSK to help boost the immune response. Curcuma longa (Turmeric) has shown promising response to prevents many diseases including current global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and neurodegenerative disorders. Curcuma longa (Haldi) a plant-based Ayurveda medicine and its content Curcumin has shown effectiveness in help fighting COVID-19 (see review in this issue by Singh et al.). Some of the other topics covered in this issue include peach cultivation in Shimla, Himachal Pradesh, India. Physical properties of soil of Aravalli hills of Rajasthan; Leaf and Sheath Blight disease of Maize Caused Rhizoctonia solani; Peptone induced pigment (a natural pigment in textile and food industry) production in Ganoderma lucidum. Algae, the principle primary producers are photosynthetic thallophytes, usually are microscopic, unicellular and colonial or multicellular. The maintenance of a healthy canal ecosystem The Journal of Plant Science Research ii Editorial depends on the abiotic properties of water and the biological diversity of ecosystem. Large scale industrialization has caused concern regarding the pollution of water. Jayasree et al. (this issue) provides ecological Study of Blue Green Algae of Canal Waters of Kerala. As Editor-in-Chief of JPSR, I feel honoured to have contributions from distinguished scientists from India and abroad. I would expect that authors follow guidelines and devote more time in articulating their ideas and discussing them in detail based on the results obtained or review of literature. The most important point in each paper remains what is the “Take home lesson”. Being UGC Care indexed journal we have added responsibility and our acceptance rate is around 70 percent. Professor Govindjee from University of Illinois at Urbana-Champaign, USA, Professor Yau from USA, Professor Ogita from Japan and Professor N. K. Dube from BHU Varanasi provide support in screening the manuscripts. Our editorial, Ms. Shyaloo and Ms. Princee Singh, Prints Publications team left no stone unturned to provide you this issue. Prof. Ashwani Kumar Editor-in-chief Alexander von Humboldt Fellow (Germany)
... β-Caryophyllene oxide is frequently found to co-occur with natural bicyclic sesquiterpene β-caryophyllene in many plant essential oils as its metabolite. Several reports have shown that both βcaryophyllene oxide and β-caryophyllene possess significant anti-cancer properties, inhibit the growth and proliferation of numerous cancer cell lines [24][25][26][27][28], and are able to enhance the antiproliferative effect of classical anticancer agents, such as 5-fluorouracil, oxaliplatin, paclitaxel, and doxorubicin [29][30][31][32]. In addition, both of these compounds were found to exhibit anti-inflammatory [33,34], analgesic [26,35], antifungal [36,37], and antibacterial activities [28,38,39]. ...
... Unfortunately, the essential oil showed a cytotoxic effect on HL-7702 cells, with IC 50 values of 19.14 ± 0.63 µg/mL. The cytotoxic activity of M. nepalensis essential oil could be attributed to the above-mentioned main compounds, as their cytotoxic effects on numerous cell lines have been widely reported [24][25][26][27][28]41,[45][46][47][48][49][50][51][52][53]91]. ...
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In response to the need for novel therapeutic strategies to combat the development of microbial resistance, plant essential oils may represent a promising alternative source. This study set out to characterize the chemical composition and assess the antibacterial potential of Myriactis nepalensis Less. essential oil (MNEO). Essential oil isolated from M. nepalensis by hydrodistillation was analyzed using a GC–MS technique. The antibacterial properties of MNEO alone and combined with antibiotics (chloramphenicol and streptomycin) were tested via the disc diffusion, microbroth dilution, and checkerboard methods. MNEO was represented by oxygenated sesquiterpenes (60.3%) and sesquiterpene hydrocarbons (28.6%), with caryophyllene oxide, spathulenol, humulene epoxide II, β-elemene, neointermedeol, and β-caryophyllene as the main compounds. MNEO exhibited a strong antibacterial effect against Gram-positive bacteria, with MIC and MBC values of 0.039 mg/mL and 0.039–0.156 mg/mL, respectively, and synergistic effects were observed in both combinations with chloramphenicol and streptomycin. Furthermore, the antibiofilm and cytotoxic activities of MNEO were also evaluated. The crystal violet assay was used for quantification of Staphylococcus aureus biofilm formation, and an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was conducted to determine cell viability. The results revealed MNEO could dose-dependently inhibit Staphylococcus aureus biofilm formation and possessed potential cytotoxic on both normal and cancer cells (IC50 values from 13.13 ± 1.90 to 35.22 ± 8.36 μg/mL). Overall, the results indicate that MNEO may have promising applications in the field of bacterial infections.
... Caryophyllene oxide is a bicyclic sesquiterpene, found as the majority compound in the SFB.3 sub-fraction with a relative abundance of 24.95%. It is mainly known for its insecticidal, antimicrobial, antifungal, analgesic, and antiparasitic properties [19]; alternatively, it also has anti-cancer properties [20][21][22] and can enhance the anti-proliferative efficacy of classical cytostatic agents [20]. The purified compound was evaluated by the MTT assay and SI (Figure 3a,c). ...
... It can only be assumed that their IC 50 is the concentration used for the tests subsequently used during the study, 50 µM. Some of these results are slightly implausible since the authors allege that OXC induces the expression of p53 in a concentration-dependent manner, even suggesting the presence of p53 protein in untreated cells [22], which cannot be true since it is known that PC-3 is a null-p53 cell line [7]. The apoptosis carried out in their investigation could be mediated by p53, thus affecting the cytotoxicity test results. ...
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Cancer treatment frequently carries side effects, therefore, the search for new selective and effective molecules is indispensable. Hymenaea courbaril L. has been used in traditional medicine in South America to treat several diseases, including prostate cancer. Leaves’ extracts from different polarities were evaluated using the 3-(4,5-methyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) cell viability assay to determine the cytotoxicity in prostate p53-null cells, followed by bio-guided fractionations to obtain the most cytotoxic fraction considering the selectivity index. The most cytotoxic fraction was analyzed by GC/MS to identify the active compounds. The majority compound, caryophyllene oxide, induced early and late apoptosis, depolarized the mitochondrial membrane, leading to several morphological changes and shifts in apoptotic proteins, and caspases were evidenced. Depolarization of the mitochondrial membrane releases the pro-apoptotic protein Bax from Bcl-xL. The apoptosis process is caspase-7 activation-dependent. Caryophyllene oxide is a safe anti-proliferative agent against PC-3 cells, inducing apoptosis with low toxicity towards normal cells.
... Moreover, it was reported that BCPO possessed methylene and epoxide exocyclic functional groups, which bind covalently to the DNA nitrogenous bases and proteins by sulfhydryl and amino groups. Thus, BCPO exhibited great potential as a signaling modulator in tumor cancer cells (Park et al., 2011). Other reports revealed that BCPO has anticancer effects on MCF-7 and prostate cancer cell lines through the indication of ROS generation, MAPK activation, and inhibition of the PI3K/AKT/ mTOR/S6K1 signaling pathway, which is vital to cell survival, proliferation, and angiogenesis of the tumor (Lo Piccolo et al., 2008). ...
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Introduction: Psidium cattleianum Sabine is a Brazilian native shrub cultivated for its edible fruit araçá (strawberry guava). P. cattleianum is recognized for health and food applications, although the essential oils (EOs) from the Egyptian inhabitant are not fully explored. The current study investigated the anti-inflammatory and cytotoxic activities of EOs from P. cattleianum leaves and flowers. Materials and methods: The EOs were obtained by three different methods viz ; the conventional hydro-distillation, microwave assisted hydro-distillation, and supercritical fluid extraction, while their analysis was accomplished using GC/MS. The derived EOs were screened for their anti-inflammatory activity in the 5-lipoxygenase, COX-1, and COX-2 enzyme based assays, while the anticancer potential was deduced from MTT cytotoxic assay, cell cycle, and western blotting analysis. Results and discussion: Among other methods, supercritical fluid extraction offered the highest EO yield, 0.62% (leaves) and 1.4% (flowers). GC/MS identified β-caryophyllene and α-humulene in both organs with high but variable percentages. The leaves demonstrated strong activity in inhibiting the 5-lipoxygenase enzyme (IC50 2.38), while the flowers, in inhibiting COX-2 (IC50 2.575). Moreover, the leaves showed potent, selective cytotoxicity to MCF-7 cells (IC50 5.32) via apoptosis by modulating the p53/Bax/Bcl2 axis. The deduced activities are possible due to the synergism between the volatile components that endorses P. cattleianum leaves’ EOs in the management of breast cancer and inflammatory disorders.
... Caryophyllene oxide: Overall, these findings suggest that CPO can interfere with multiple signaling cascades involved in tumorigenesis and used as a potential therapeutic candidate for both the prevention and treatment of cancer (Park et al., 2011). ...
Preprint
Black horehound (Ballota nigra L.) is one of the important medicinal plants, which is a rich source of health-promoting essential oils. Salinity stress affects plant development and alters the quality and quantity of plants extracts and their composition. This study was aimed to investigate the effect of salinity on morphological, physiological characteristics, and secondary metabolites of B. nigra under greenhouse, and in vitro culture conditions. The plants were treated with different concentrations of NaCl (25, 50, 75, 100 mM) and fresh and dry weight of leaf and stem were measured as well as morphological characteristics of the plant. Plant growth was reduced with the increased salinity concentrations. The results showed that all growth-related traits and SPAD were decreased both in vivo and in vitro. Additionally, increased salt concentration affected the cell membrane integrity. Total phenolics content of plants growing in the greenhouse, increased by 21% at 50 mM NaCl, but at higher stress levels (100 mM NaCl), the amounts were decreased significantly. Total flavonoids contents followed similar patterns, with a slight difference. In addition, the maximum and minimum total phenolics contents of plants growing under in vitro condition were observed at 50 mM NaCl and control treatments, respectively. Increasing the salt concentration significantly affected the total flavonoids content, and as a result, the highest amount was observed in 50 and 75 mM NaCl treatments. Antioxidant activity was also measured. Among the NaCl treatments, the highest DPPH scavenging activities (IC50) under greenhouse and in vitro conditions were detected at 50 mM and 25 mM concentrations, respectively. In general, based on the results, with increasing the salinity level to 75 mM, the activities of CAT and APX were significantly upregulated in both greenhouse and in vitro culture conditions. A correlation between total phenolics and flavonoids contents as well as antioxidant activity were obtained. With shifting salinity stress, the type and the amount of the identified essential oil compounds changed. Compounds such as styrene, tridecanol, germacrene-D, beta-Ionone, beta-bisabolene, and caryophyllene oxide increased compared to the controlled treatment.
... An additional work evidenced that a vesicle-mediated transport from the ER to the plasma membrane is involved in the subcellular movement of the sesquiterpenes copaene and β-caryophyllene in Sauromatum guttatum flowers [114]. β-Caryophyllene is a potential toxic volatile since, in the cytosol, it can react with proteins, leading to the formation of caryophyllene oxide (CPO) [115]. CPO induces increased reactive oxygen species (ROS) generation from mitochondria, leading to the induction of degenerative processes [112]. ...
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Contrary to the biosynthetic pathways of many terpenoids, which are well characterized and elucidated, their transport inside subcellular compartments and the secretion of reaction inter-mediates and final products at the short-(cell-to-cell), medium-(tissue-to-tissue), and long-distance (organ-to-organ) levels are still poorly understood, with some limited exceptions. In this review, we aim to describe the state of the art of the transport of several terpene classes that have important physiological and ecological roles or that represent high-value bioactive molecules. Among the tens of thousands of terpenoids identified in the plant kingdom, only less than 20 have been characterized from the point of view of their transport and localization. Most terpenoids are secreted in the apoplast or stored in the vacuoles by the action of ATP-binding cassette (ABC) transporters. However, little information is available regarding the movement of terpenoid biosynthetic intermediates from plastids and the endoplasmic reticulum to the cytosol. Through a description of the transport mechanisms of cytosol-or plastid-synthesized terpenes, we attempt to provide some hypotheses, suggestions, and general schemes about the trafficking of different substrates, intermediates, and final products, which might help develop novel strategies and approaches to allow for the future identification of terpenoid transporters that are still uncharacterized.
... It is shown that BCP is a strong CB2 agonist and has anti-inflammatory effects in DSS-induced colitis mouse models [53,54]. The oxidized BCP can alter cancer-related pathways, such as MAPK, STATS pathways, by induction of reactive oxygen species generation in prostate and breast cancer cell lines independent of endocannabinoid system machinery [53,55]. The signal intensity of oxidized BCP was significantly higher in RV-outdoor samples compared to indoor groups. ...
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Interest in cultivating cannabis for medical and recreational purposes is increasing due to a dramatic shift in cannabis legislation worldwide. Therefore, a comprehensive understanding of the composition of secondary metabolites, cannabinoids, and terpenes grown in different environmental conditions is of primary importance for the medical and recreational use of cannabis. We compared the terpene and cannabinoid profiles using gas/liquid chromatography and mass spectrometry for commercial cannabis from genetically identical plants grown indoors using artificial light and artificially grown media or outdoors grown in living soil and natural sunlight. By analyzing the cannabinoids, we found significant variations in the metabolomic profile of cannabis for the different environments. Overall, for both cultivars, there were significantly greater oxidized and degraded cannabinoids in the indoor-grown samples. Moreover, the outdoor-grown samples had significantly more unusual cannabinoids, such as C4- and C6-THCA. There were also significant differences in the terpene profiles between indoor- and outdoor-grown cannabis. The outdoor samples had a greater preponderance of sesquiterpenes including β-caryophyllene, α-humulene, α-bergamotene, α-guaiene, and germacrene B relative to the indoor samples.
... Presence of phytosteroids in M. phillippensis accounts for the modulatory effect in the expression of steroidogenic genes. Among obtained compounds, caryophyllene possessed anticancer activity by inhibiting proliferation of MCF-7 cells and reduced cholesterol levels [27] . Methyl 8,11,14 Heptadecatrienoate, an aliphatic fatty acid found in methanol extracts of Glycosmis mauritiana have antioxidant, hypochloesterolemic activities [28] . ...
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The role of oestrogen in the development of breast cancer is well documented. The aberrant expression of genes involved in oestrogen hormone synthesis can be one of the causes of breast cancer. Suppression of these genes is considered a therapeutic option for the treatment of breast cancer. In the present study, we evaluated the effect of a methanolic extract of Mallotus phillippensis leaves on the expression of CYP19 and StAR genes in MCF-7 breast cancer cell lines. The half maximal inhibitory concentration (IC50) of the extract was found to be 190 µg/mL. MCF-7 cells treated with half IC50, IC50 and double IC50 of the extract that is 95, 190 and 380 µg/mL, was used for evaluating the effect on the gene. Methanolic extract of M. phillippensis at double IC50 doses, upregulated the expression of StAR and CYP 19 genes, whereas at half IC50 and IC50 doses downregulated StAR and CYP 19 gene expression. The gas chromatography mass spectrometry analysis revealed the presence of phytosterols, fatty acid analogues and terpenoids in the extract which contributed to differential expression of StAR and CYP 19 genes. The confirmation of detected compounds was carried out by Fourier transform infrared spectroscopy analysis. From this study, it is inferred that higher doses of methanolic extract of Mallotus phillippensis can be used for treatment of the oestrogen deficient conditions leading to infertility while at lower doses significantly reduces StAR and CYP 19 gene expression can be recommended for the treatment of breast cancer.
... Studies by others have shown that mTOR, a crucial stress regulator, primarily encourages oxidative metabolism and mitochondrial biogenesis in a context dependent manner [55]. NADPH oxidase activation and mitochondrial dysfunction increased ROS generation through Akt-mTOR signaling [26]. It is known that mTOR plays a crucial role in maintaining oxidative equilibrium, is involved in the degradation of NRF2, and acts upstream of NRF2 in Ang II-induced cardiac hypertrophy [27,56]. ...
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Patients with type two diabetes mellitus (T2DM) are at increased risk for cardiovascular diseases. Impairments of endothelin-1 (ET-1) signaling and mTOR pathway have been implicated in diabetic cardiomyopathies. However, the molecular interplay between the ET-1 and mTOR pathway under high glucose (HG) conditions in H9c2 cardiomyoblasts has not been investigated. We employed MTT assay, qPCR, western blotting, fluorescence assays, and confocal microscopy to assess the oxidative stress and mitochondrial damage under hyperglycemic conditions in H9c2 cells. Our results showed that HG-induced cellular stress leads to a significant decline in cell survival and an impairment in the activation of ETA-R/ETB-R and the mTOR main components, Raptor and Rictor. These changes induced by HG were accompanied by a reactive oxygen species (ROS) level increase and mitochondrial membrane potential (MMP) loss. In addition, the fragmentation of mitochondria and a decrease in mitochondrial size were observed. However, the inhibition of either ETA-R alone by ambrisentan or ETA-R/ETB-R by bosentan or the partial blockage of the mTOR function by silencing Raptor or Rictor counteracted those adverse effects on the cellular function. Altogether, our findings prove that ET-1 signaling under HG conditions leads to a significant mitochondrial dysfunction involving contributions from the mTOR pathway.
... To further identify the mediators responsible for the cytoprotective action of CTPS on cisp-treated macrophages, we showed that CTPS suppressed the cisp-induced apoptotic pathways via reducing ROS production and MTP loss. These findings are similar to those of earlier studies, which reported the role of ROS, MTP, and DNA fragmentation in the initiation and execution of apoptosis via mitochondria [39][40][41]. In view of these findings, it may be speculated that the cytoprotective effect of CTPS against cisp-induced cytotoxicity is mediated by suppressing apoptotic pathways and regulating the mitochondrial dysfunction in cisp-treated macrophages [39,42]. ...
... using Student-Newman-Keuls test. Park et al., 2011). In this study, cytotoxicity of CPO was shown in fibrosarcoma cells. ...
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When cancer cells transform into malignant tumors, they gain the ability to ignore growth‐inhibiting signals, have endless reproduction potential, resist apoptosis, and induce angiogenesis and invade other tissues. Matrix metalloproteinases (MMPs) allow tumor cells to move into surrounding tissues in many malignancies, but metastasis is blocked by MMPs inhibitors. Therefore, the effect of β‐caryophyllene oxide (CPO) contained in Piper nigrum on Mitogen‐activated protein kinase (MAPKs) related to MMPs signaling pathways in human fibrosarcoma was examined in HT1080 cells. The effect of CPO on cell viability was performed using the MTT assay. Cytotoxicity was observed in the presence of CPO above 16 μM. Next, gelatin zymography was performed in the cells activated with phorbol‐12‐myristate‐13‐acetate (PMA). It was found that CPO at 32 μM reduced MMP‐9 activity by 28% and MMP‐2 activity by 60%. To confirm the effect of CPO on MMPs, Western blot analyses for MMP‐2, MAPKs were carried out in this study. The expression level of MMP‐2 was reduced by 45% in the presence of CPO at 32 μM, but those of p‐p38 and p‐ERK were reduced by 50% and 40%, respectively. CPO decreased the expression levels of MMP‐2 and MMP‐9 in the immunofluorescence staining assay. Finally, an invasion assay was performed in PMA‐treated human fibrosarcoma cells. It was demonstrated that CPO reduced cell invasion of HT1080 cells in a dose‐dependent manner starting at a concentration of 2 μM. The above results suggest that CPO could be used as a potential candidate for the treatment of metastasis by inhibiting MMP‐2, p‐p38 and p‐ERK. Practical applications Cancer makes it easier for cells to spread to other tissue via blood and lymph systems. Tumor cells deplete nutrients and induce angiogenesis, which penetrates and spreads to other parts of the body. As a result, the effect of CPO against cell invasion was evaluated in this study. CPO reduced cancer cell invasion by inactivating p‐ERK and p‐p38, according to the findings. MMP‐2 and MMP‐9 activation and protein expression were also decreased by CPO. As a result, CPO might be used as an alternate treatment agent for preventing metastasis.
... α-caryophllene has been reported to be cytotoxic against human breast adenocarcinoma cell line (MCF-7) and its anticancer effect was observed to be potentiated by the presence of β-caryophyllene (Legault and Pichette, 2007). βcaryophyllene reportedly suppressed PC-3-prostate cancer cell and MCF-7-breast cancer cell proliferation in a dose-dependent manner (Park et al., 2011) by inhibiting signaling pathways in these cells responsible for cell survival, proliferation, and angiogenesis (LoPiccolo et al., 2008). The remarkable activity displayed by fraction F1 therefore, may be as a result of synergistic effects of these components found in it. ...
Article
Background: Volatile oils have found use locally in the management of many diseases including tumor-related ailments. Due to the short-comings of orthodox medicine, there is a need to source for alternative drugs with better effects. Callistemon citrinus oil contains some bioactive compounds which are useful in treating many diseases. This study was designed to examine the chemical composition and cytotoxic efficacy of this plant oil.Method: Callistemon citrinus volatile oil was extracted from fresh leaves using a Clavenger apparatus by hydro-distillation method. Preliminary cytotoxic screening was carried out with brine shrimp at 10-1000 μg/mL. The essential oil was further tested on breast (AU 565) and cervical (HeLa) cancer cell lines at 50 μg /mL using MTT assay. Column chromatography of the oil was carried out and the resulting fractions subjected to biological testing. GCMS analysis was carried out on the oil and the most active fraction.Results: The oil produced concentration- dependent activity with an LC50 of 528.48 μg/mL in the brine shrimp mortality assay. The oil also produced -7.60 and +11.80 % inhibitions against HeLa and AU 565 cells respectively. Column fraction F1 produced the highest activity against AU 565 cells with 70.44 % inhibition and an IC50 of 15.96 μg/mL. C. citrinus oil revealed the presence of cineole (36.06 %) and α-pinene (21.41 %) as the major components while 1,1'-(5-hydroxy-2,2-dimethylbicyclo[4.1.0]heptane-1,7-diyl)bis-, (1α,5β,6α,7α)-ethanone (24.89 %.) was the most abundant in the active fraction.Conclusion: C. citrinus volatile oil has cytotoxic potential and is a good candidate for further in vivo studies.
... No information is available on DLZ but another benzodiazepine, the diazepam, has proven pro-oxidative effects (Musavi and Kakkar, 1998). ROS production can activate the MAPK signaling pathways, which further activates several inflammatory cytokines (Park et al., 2011). In Xenopus embryos, overexpression of tnfα, il1b, and p65 is registered which explains edema and developmental changes. ...
Article
Benzodiazepines, psychotropics drugs used for treating sleep disorders, anxiety and epilepsy, represent a major class of emerging water pollutants. As occurs for other pharmaceutical residues, they are not efficiently degraded during sewage treatment and persist in effluent waters. Bioaccumulation is already reported in fish and small crustaceans, but the impact and consequences on other “non-target” aquatic species are still unclear and nowadays of great interest. In this study, we investigated the effects of a pharmaceutical preparation containing the benzodiazepine delorazepam on the embryogenesis of Xenopus laevis, amphibian model species, taxa at high risk of exposure to water contaminants. Environmental (1 μg/L) and two higher (5 and 10 μg/L) concentrations were tested on tadpoles up to stage 45/46. Results demonstrate that delorazepam interferes with embryo development and that the effects are prevalently dose-dependent. Delorazepam reduces vitality by decreasing heart rate and motility, induces marked cephalic and abdominal edema, as well as intestinal and retinal defects. At the molecular level, delorazepam increases ROS production, modifies the expression of some master developmental genes and pro-inflammatory cytokines. The resulting stress condition significantly affects embryos’ development and threatens their survival. Similar effects should be expected as well in embryos belonging to other aquatic species that have not been yet considered targets for these pharmaceutical residues.
... Park et al reported a significant inhibitory effect of caryophyllene oxide on cellular growth and induction of apoptosis by downregulation of the PI3K/AKT/mTOR/S6K1 signaling cascade in BCa. 39 7-hydroxycadalene derived from Heterotheca inuloides displayed anti-NF-κB activity in vitro against six human cancer cell lines. 40 7-hydroxycadalene also displayed cytotoxic ability in MCF7 cell lines. ...
Article
Background Breast cancer is the most common cancer in women worldwide. Use of homeopathic medicines for the treatment of cancers has increased in the last several years. Arnica montana is an anti-inflammatory homeopathic medicine used in traumatic conditions and because of this property we performed investigations for its potential as a chemotherapeutic agent against breast cancer. Methods An ethanolic extract of Arnica montana (mother tincture, MT), prepared according to the Homoeopathic Pharmacopoeia of India, was characterized by gas chromatography–mass spectroscopy (GC–MS), followed by computational (in silico) analysis using molecular docking, to identify specific compounds that can bind and modulate the activity of key proteins involved in breast cancer survival and progression. To validate the in silico findings, in a controlled experiment breast cancer cells (MCF7) were treated in vitro with Arnica montana and the cytotoxic effects assessed by flowcytometry, fluorescence microscopy, scratch assay, clonogenic potential and gene expression analysis. Results Phytochemical characterization of ethanolic extract of Arn MT by GC–MS allowed identification of several compounds. Caryophyllene oxide and 7-hydroxycadalene were selected for molecular docking studies, based on their potential drug-like properties. These compounds displayed selective binding affinity to some of the recognized target proteins of breast cancer, which included estrogen receptor alpha (ERα), progesterone receptor (PR), epidermal growth factor receptor (EGFR), mTOR (mechanistic target of rapamycin) and E-cadherin. In vitro studies revealed induction of apoptosis in MCF7 cells following treatment with Arn MT. Furthermore, treatment with Arn MT revealed its ability to inhibit migration and colony forming abilities of the cancer cells. Conclusion Considering the apoptotic and anti-migratory effects of Arnica montana in breast cancer cells in vitro, there is a need for this medicine to be further validated in an in vivo model.
... Therefore, it can bind covalently to proteins and DNA bases by the sulfhydryl and amino groups. So, caryophyllene oxide has revealed high potential as a signaling modulator for tumor cancer cells [12,18]. ...
Article
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Eugenia patrisii Vahl is a native and non-endemic myrtaceous species of the Brazilian Amazon. Due to few botanical and phytochemical reports of this species, the objective of the present work was to evaluate the seasonal variability of their leaf essential oils, performed by GC and GC-MS and chemometric analysis. The results indicated that the variation in oil yields (0.7 ± 0.1%) could be correlated with climatic conditions and rainy (R) and dry seasons (D). (E)-caryophyllene (R = 17.1% ± 16.0, D = 20.2% ± 17.7) and caryophyllene oxide (R = 30.1% ± 18.4, D = 14.1% ± 19.3) are the major constituents and did not display significant differences between the two seasons. However, statistically, a potential correlation between the main constituents of E. patrisii essential oil and the climatic parameters is possible. It was observed that the higher temperature and insolation rates and the lower humidity rate, which are characteristics of the dry season, lead to an increase in the (E)-caryophyllene contents, while lower temperature and insolation and higher humidity, which occur in the rainy season, lead to an increase in the caryophyllene oxide content. The knowledge of variations in the E. patrisii essential oil composition could help choose the best plant chemical profile for medicinal purposes. Citation: da Cruz, E.d.N.S.; Peixoto, L.d.S.; da Costa, J.S.; Mourão, R.H.V.; do Nascimento, W.M.O.; Maia, J.G.S.; Setzer, W.N.; da Silva, J.K.; Figueiredo, P.L.B.
... Therefore, it can bind covalently to proteins and DNA bases by the sulfhydryl and amino groups. So, caryophyllene oxide has revealed high potential as a signaling modulator for tumor cancer cells [12,18]. ...
Article
Full-text available
Eugenia patrisii Vahl is a native and non-endemic myrtaceous species of the Brazilian Amazon. Due to few botanical and phytochemical reports of this species, the objective of the present work was to evaluate the seasonal variability of their leaf essential oils, performed by GC and GC-MS and chemometric analysis. The results indicated that the variation in oil yields (0.7 ± 0.1%) could be correlated with climatic conditions and rainy (R) and dry seasons (D). (E)-caryophyllene (R = 17.1% ± 16.0, D = 20.2% ± 17.7) and caryophyllene oxide (R = 30.1% ± 18.4, D = 14.1% ± 19.3) are the major constituents and did not display significant differences between the two seasons. However, statistically, a potential correlation between the main constituents of E. patrisii essential oil and the climatic parameters is possible. It was observed that the higher temperature and insolation rates and the lower humidity rate, which are characteristics of the dry season, lead to an increase in the (E)-caryophyllene contents, while lower temperature and insolation and higher humidity, which occur in the rainy season, lead to an increase in the caryophyllene oxide content. The knowledge of variations in the E. patrisii essential oil composition could help choose the best plant chemical profile for medicinal purposes. Citation: da Cruz, E.d.N.S.; Peixoto, L.d.S.; da Costa, J.S.; Mourão, R.H.V.; do Nascimento, W.M.O.; Maia, J.G.S.; Setzer, W.N.; da Silva, J.K.; Figueiredo, P.L.B.
... mTOR, an important regulator of cellular stress, mainly promotes oxidative metabolism and mitochondrial biogenesis (Sengupta et al., 2010). Activation of Akt-mTOR signaling enhanced ROS production via NADPH oxidase and mitochondrial dysfunction (Park et al., 2011). In this study, DBZ inhibited stress-induced mTOR phosphorylation, and L -leucine nearly eliminated the DBZ-mediated attenuation of oxidative stress and ER stress, indicating that mTOR was pivotal in the DBZ-mediated inhibition of oxidative stress and NRF2 degradation. ...
Article
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Tanshinol borneol ester (DBZ) exerts anti-atherosclerotic and anti-inflammatory effects. However, its effects on cardiac hypertrophy are not well understood. In this work, we investigated the treatment effects and potential mechanisms of DBZ on the hypertrophic heart under oxidative stress and endoplasmic reticulum (ER) stress. A hypertrophic model was established in rats using transverse-aortic constriction (TAC) surgery and in neonatal rat cardiomyocytes (NRCMs) using angiotensin II (Ang II). Our results revealed that DBZ remarkably inhibited oxidative stress and ER stress, blocked autophagy flow, and decreased apoptosis in vivo and in vitro through nuclear NRF2 accumulation, and enhanced NRF2 stability via regulating the mTOR/β-TrcP/NRF2 signal pathway. Thus, DBZ may serve as a promising therapeutic for stress-induced cardiac hypertrophy.
... β-bisabolene is most commonly used in the treatment of breast cancers [48]. Caryophyllene oxide interferes with multiple signaling cascades involved in tumorigenesis and is used to prevent and treat cancer [49]. A terpenoid, sesquiphellandrene, and heterocyclic organic compound, benzimidazole, demonstrated cytotoxic activity against various cancer cell lines [50]. ...
Article
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Black horehound (Ballota nigra L.) is one of the most important medicinal plants, as a rich source of health-promoting essential oils and metabolites. Salinity stress affects plant development and alters antioxidant activity and plant metabolite composition. The present research aimed to study the effect of salinity on physiological and biochemical changes and metabolites of B. nigra under greenhouse and in vitro culture conditions. The plants were treated with different concentrations of NaCl (25, 50, 75, 100 mM), and morphological characteristics of the plant were measured. The growth-related traits and soil plant analysis development (SPAD) were decreased both in vivo and in vitro. Additionally, increased salt concentration negatively affected the cell membrane integrity. The total phenolic content and flavonoids of plants growing in the greenhouse increased by 21% at 50 mM of NaCl, but the amounts decreased significantly at higher stress levels (100 mM of NaCl). Antioxidant activity was also measured. Among the NaCl treatments, the most increased DPPH scavenging activities (IC50) under greenhouse and in vitro conditions were detected at mild salinity stress, but the activity significantly decreased in higher salinity treatments (i.e., 75 and 100 mM). In general, with increasing the salinity level to 75 mM, the activities of CAT and APX were significantly upregulated in both greenhouse and in vitro culture conditions. A correlation between total phenolics and flavonoids contents as well as antioxidant activity was obtained. Salinity level caused a shift in the metabolite expression. Mild salinity stress elevated the metabolites involved in anticancer and anti-inflammatory activities, such as β-ionone and caryophyllene oxide. However, the higher salt stress resulted in a significant reduction in their expression. Differential expression of metabolites to various levels of salt stress can be further exploited for the in vitro biosynthesis of metabolites.
... β-Caryophyllene oxide has been reported to prevent tumor growth and induces apoptosis through the suppression of Phosphatidylinositol-3-kinase (PI3K)/AKT/ mammalian target of the rapamycin (mTOR)/S6 Kinase 1 (S6K1) pathways and ROS-mediated mitogen-activated protein kinases (MAPKs) activation. 44 However, the βcaryophyllene on NSCLC apoptosis is still seldom reported. Previous work also suggests that β-caryophyllene may induce cell cycle arrest and lead to apoptosis. ...
Article
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Background: β-Caryophyllene is the main ingredient of chilli pepper and used for the prevention of various cancers, while the molecular mechanism for its effects on non-small cell lung cancer (NSCLC) remains unclear. Methods: NSCLC cell lines A549 and NCI-H1299 were treated with β-Caryophyllene and miR-659-3p (a potential tumor suppressor) mimic or siRNA. The levels of miR-659-3p, sphingosine kinase 1 (SphK1), apoptotic factors and oxidative stress factors were investigated. Results: β-Caryophyllene inhibited NSCLC growth, promoted their apoptotic rate, increased the level of miR-659-3p, apoptotic factors (cleaved caspase-3 and BAX), antioxidant factors (SOD, CAT and GPx) and reduced the level of oxidative stress (ROS and NO) and SphK1. miR-659-3p mimic and siRNA affected NSCLC growth, their apoptosis, and biochemical indices. Conclusion: β-Caryophyllene of chilli pepper exerts inhibitory activity in NSCLC cells possibly by affecting miR-659-3p-targeted SphK1.
... β-caryophyllene potentiated the anticancer activity of paclitaxel by facilitating the passage of paclitaxel through the plasma membrane [344]. βcaryophyllene induced ionstitutive activation of PI3K/AKT/mTOR/S6K1 signaling and activation of ERK, JNK, and p38 MAPK in tumor cells [345], suppressed constitutive STAT3 activation in breast cancer cell lines and found cytotoxic to MDA-MB-231 [346]. Eugenol inhibits the cell proliferation and induces the apoptosis in human MCF-7 breast cancer cells [347]. ...
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Many lay people along with some so called “key opinion leaders” have a common slogan “There's no answer for cancer”. Again, mistake delays proper treatment and make situation worse, more often. Compliance is crucial to obtain optimal health outcomes, such as cure or improvement in QoL. Patients may delay treatment or fail to seek care because of high out-of- pocket expenditures. Despite phenomenal development, conventional therapy falls short in cancer management. There are two major hurdles in anticancer drug development: dose-limiting toxic side effects that reduce either drug effectiveness or the QoL of patients and complicated drug development processes that are costly and time consuming. Cancer patients are increasingly seeking out alternative medicine and might be reluctant to disclose its use to their oncology treatment physicians. But there is limited available information on patterns of utilization and efficacy of alternative medicine for patients with cancer. As adjuvant therapy, many traditional medicines shown efficacy against brain, head and neck, skin, breast, liver, pancreas, kidney, bladder, prostate, colon and blood cancers. The literature reviews non-pharmacological interventions used against cancer, published trials, systematic reviews and meta-analyses.
... Moreover, high expression of survivin has been universally associated with resistance to apoptosis, higher tumor grade, increased metastasis, and resistance to therapy in virtually every human tumor [37]. Our finding of survivin downregulation is in accordance with the previous report by Park et al., wherein survivin expression was remarkably decreased in both breast and prostate cancer cells after treatment with BCP oxide [38]. Apart from survivin and XIAP, BCP exposure also decreased the expression of the heat shock protein, HSP60, which has been reported to inhibit activation of mitochondria-mediated apoptosis through halting the release of cytochrome C and up-regulation of survivin in colon cancer [39]. ...
Article
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Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels. Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer. Computational structural analysis and an apoptosis antibody array were also performed to understand the molecular players underlying this effect. BCP exhibited strong anti-angiogenic activity by blocking the migration of endothelial cells, tube-like network formation, suppression of vascular endothelial growth factor (VEGF) secretion from human umbilical vein endothelial cells and sprouting of rat aorta microvessels. BCP has a probable binding at Site#0 on the surface of VEGFR2. Moreover, BCP significantly deformed the vascularization architecture compared to the negative control in a chick embryo chorioallantoic membrane assay. BCP showed a remarkable reduction in tumor size and fluorescence molecular tomography signal intensity in all the mice treated with BCP, in a dose-dependent relationship, in ectopic and orthotopic tumor xenograft models, respectively. The histological analysis of the tumor from BCP-treated mice revealed a clear reduction of the density of vascularization. In addition, BCP induced apoptosis through downregulation of HSP60, HTRA, survivin, and XIAP, along with the upregulation of p21 expressions. These results suggest that BCP acts at multiple stages of angiogenesis and could be used as a promising therapeutic candidate to halt the growth of colorectal tumor cells.
... The phosphoinositide 3-kinase (PI3K) pathway is a multistep, tightly controlled and widely involved survival cascade in almost all kind of tumors. It can be activated in response to various GFs and proinflammatory cytokines like vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and PDGF, and cytokines such as IL-1β, IL-6 and IL-8 that cause alternations in various cellular processes, including cell growth, cell cycle progression, migration, invasion, angiogenesis and metastasis [35,36]. The PI3K, which consists of two major subunits p110 (catalytic) and p85 (regulatory) along with either tightly coupled receptor tyrosine kinases (RTKs) or adapter molecules that triggered the activation of downstream cascade components that finally regulate different cellular functions. ...
Article
Reactive oxygen species play crucial role in biological homeostasis and pathogenesis of human diseases including cancer. In this line, now it has become evident that ROS level/concentration is a major factor in the growth, progression and stemness of cancer cells. Moreover, cancer cells maintain a delicate balance between ROS and antioxidants to promote pathogenesis and clinical challenges via targeting a battery of signaling pathways converging to cancer hallmarks. Recent findings also entail the therapeutic importance of ROS for the better clinical outcomes in cancer patients as they induce apoptosis and autophagy. Moreover, poor clinical outcomes associated with cancer therapies are the major challenge and use of natural products have been vital in attenuation of these challenges due to their multitargeting potential with less adverse effects. In fact, most available drugs are derived from natural resources, either directly or indirectly and available evidence show the clinical importance of natural products in the management of various diseases, including cancer. ROS play a critical role in the anticancer actions of natural products, particularly phytochemicals. Benzophenanthridine alkaloids of the benzyl isoquinoline family of alkaloids, such as sanguinarine, possess several pharmacological properties and are thus being studied for the treatment of different human diseases, including cancer. In this article, we review recent findings, on how benzophenanthridine alkaloid-induced ROS play a critical role in the attenuation of pathological changes and stemness features associated with human cancers. In addition, we highlight the role of ROS in benzophenanthridine alkaloid-mediated activation of the signaling pathway associated with cancer cell apoptosis and autophagy.
... They found that apoptosis is produced through suppression of PI3K/AKT/mTOR/S6K1 pathways and also following ROSmediated MAPKs activation. The first signaling pathway is not only conducting toward apoptosis but is closely related to angiogenesis and the second pathway ROS-mediated mitogen-activated protein kinases activation regulates diverse cellular actions as proliferation, motility, and survival [85]. ...
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Cell biology, plant-based extracts, structural chemistry, and laboratory in vitro or in vivo experiments are the principal aspects or interfaces that can contribute to discovering new possibilities in cancer therapy and to developing improved chemotherapeutics. Forestry residues can be used for their wealthy resource in polyphenols and other phytoconstituents known for anticancer properties. This review is designed to bring together information on the in vitro or in vivo anticancer potential of woody vascular plants especially the bark extracts (BE) and biosynthesized metallic nanoparticles (BMN) using bark extracts. Type of extracts, main phytoconstituents found in extracts responsible for the anticancer activity, and targeted cancerous cell lines were followed. The literature data were collected via Clarivate Analytics, Science Direct, PubMed, and Google Academic (2011–2021). The search terms were: bark extracts, metallic nanoparticles, silver nanoparticles, gold nanoparticles, anticancer, cytotoxic activity, antiproliferative effect, and antimetastatic potential in vitro and in vivo. All of the search terms listed above were used in different combinations. The literature data highlight the efficaciousness of the BE and BMN as anticancer agents in in vitro experiments and showed the mechanism of action and their advantage of nontoxicity on normal cells. In vitro testing has shown promising results of the BE and BMN effect on different cancer cell lines. In vivo testing is lacking and more data is necessary for drug development on animal models.
... Eugenol is a volatile phenol originally used in dentistry with local antiseptic and analgesic effects, which emerged recently as a modulator of chronic inflammation, oxidative stress, and mitochondrial dysfunction [14]. β-Caryophyllene and its oxide are sesquiterpenes which were recently studied extensively for their eminent activities against tumorigenesis, nephrotoxicity, hepatic fibrosis, neurodegenerative and metabolic diseases [15][16][17]. These compounds share some pharmacological similarities, but also have their own bioactive characteristics, of which synergistic effects on different targets conduct the overall efficacy of A. argyi. ...
Article
Artemisia argyi is commonly used as a remedy for gynecological and respiratory disease in traditional Chinese medicine. The essential oil is considered as the major active ingredients of A. argyi, mainly composing of eucalyptol, α-thujone, camphor, borneol, bornyl acetate, eugenol, β-caryophyllene, and caryophyllene oxide, while limited study addresses the in vivo disposition of these volatile ingredients. In present study, a rapid, sensitive and selective GC-MS/MS method has been developed and validated for the quantification of the eight volatile constituents in rat plasma and tissues after orally dosed with the essential oil of Artemisiae Argyi Folium (AAEO) using naphthalene as an internal standard (IS). The analytes were extracted from biosamples by liquid-liquid extraction with hexane/ethyl acetate. The GC separation was achieved on a TG-5SILMS column (30 m × 0.25 mm, 0.25 μm film thickness) and MS detection was performed on selective reaction monitoring (SRM) mode. The assay had a lower limit of quantification (LLOQ) less than 2 ng/ml for the analytes with good linearity (r≥0.9907). Their disposition profile in rat plasma and tissues was characterized after orally given AAEO, and the data revealed the analytes underwent rapid absorption from GI tract and mainly transferred to the liver, heart, kidney, lung, and spleen with prompt elimination. The results provided a meaningful basis for guiding the pharmacodynamic study and clinical applications of this herbal medicine.
... To further identify the mediators responsible for the cytoprotective action of CTPS on cisp-treated macrophages, we showed that CTPS suppressed the cisp-induced apoptotic pathways via reducing ROS production and MTP loss. These findings are similar to those of earlier studies, which reported the role of ROS, MTP, and DNA fragmentation in the initiation and execution of apoptosis via mitochondria [39][40][41]. In view of these findings, it may be speculated that the cytoprotective effect of CTPS against cisp-induced cytotoxicity is mediated by suppressing apoptotic pathways and regulating the mitochondrial dysfunction in cisp-treated macrophages [39,42]. ...
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Although cisplatin is one of most effective chemotherapeutic drugs that is widely used to treat various types of cancer, it can cause undesirable damage in immune cells and normal tissue because of its strong cytotoxicity and non-selectivity. This study was conducted to investigate the cytoprotective effects of Cudrania tricuspidata fruit-derived polysaccharides (CTPS) against cisplatin-induced cytotoxicity in macrophages, lung cancer cell lines, and a mouse model, and to explore the possibility of application of CTPS as a supplement for anticancer therapy. Both cisplatin alone and cisplatin with CTPS induced a significant cytotoxicity in A549 and H460 lung cancer cells, whereas cytotoxicity was suppressed by CTPS in cisplatin-treated RAW264.7 cells. CTPS significantly attenuated the apoptotic and necrotic population, as well as cell penetration in cisplatin-treated RAW264.7 cells, which ultimately inhibited the upregulation of Bcl-2-associated X protein (Bax), cytosolic cytochrome c, poly (adenosine diphosphateribose) polymerase (PARP) cleavage, and caspases-3, -8, and -9, and the downregulation of B cell lymphoma-2 (Bcl-2). The CTPS-induced cytoprotective action was mediated with a reduction in reactive oxygen species production and mitochondrial transmembrane potential loss in cisplatin-treated RAW264.7 cells. In agreement with the results obtained above, CTPS induced the attenuation of cell damage in cisplatin-treated bone marrow-derived macrophages (primary cells). In in vivo studies, CTPS significantly inhibited metastatic colonies and bodyweight loss as well as immunotoxicity in splenic T cells compared to the cisplatin-treated group in lung metastasis-induced mice. Furthermore, CTPS decreased the level of CRE and BUN in serum. In summation, these results suggest that CTPS-induced cytoprotective action may play a role in alleviating the side effects induced by chemotherapeutic drugs.
... Large amounts of this compound have also been identified in oil from L. maculatum aerial parts [109]. This component exhibits antimicrobial [85], antifungal [110], and insecticidal properties [111,112] and induces apoptosis of neoplastic cells [113]. ...
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The aim of this study was to conduct a histochemical analysis to localize lipids, terpenes, essential oil, and iridoids in the trichomes of the L. album subsp. album corolla. Morphometric examinations of individual trichome types were performed. Light and scanning electron microscopy techniques were used to show the micromorphology and localization of lipophilic compounds and iridoids in secretory trichomes with the use of histochemical tests. Additionally, the content of essential oil and its components were determined using gas chromatography-mass spectrometry (GC-MS). Qualitative analyses of triterpenes carried out using high-performance thin-layer chromatography (HPTLC) coupled with densitometric detection, and the iridoid content expressed as aucubin was examined with spectrophotometric techniques. We showed the presence of iridoids and different lipophilic compounds in papillae and glandular and non-glandular trichomes. On average, the flowers of L. album subsp. album yielded 0.04 mL/kg of essential oil, which was dominated by aldehydes, sesquiterpenes, and alkanes. The extract of the L. album subsp. album corolla contained 1.5 × 10−3 ± 4.3 × 10−4 mg/mL of iridoid aucubin and three triterpenes: oleanolic acid, β-amyrin, and β-amyrin acetate. Aucubin and β-amyrin acetate were detected for the first time. We suggest the use of L. album subsp. album flowers as supplements in human nutrition.
Article
The genus Ziziphora of the family Lamiaceae is well known for the medicinal properties of its species. Ziziphora persica is an edible medicinal plant, which is widely distributed in countries of Iran, Turkey, Kazakhstan and Azaerbaidzhan and is famed as a wild vegetable with notable aroma and flavor. In Iranian folk medicine, Ziziphora species has been also used as infusions for various purposes such as sedative, stomachic and carminative among others. The genus Ziziphora belongs to the Lamiaceae family consists of four species (Z. clinopodioides, Z. capitata, Z. persica and Z. tenuior) that widespread all over Iran. Ziziphora with common Persian name ‘kakuti-e kuhi’ comprised nine subspecies native to Iran. The composition and antibacterial and antioxidant activity of the essential oil and various extracts of Ziziphora persica were reported. This review presents and overview on the Eco-phytochemistry and Ethnobotany knowledge of Ziziphora persica and provides a deeper insight into phytochemistry of this specie. Relevant data were obtained through systematic electronic searches from various scientific databases including the institute of scientific information (ISI)-web of science, mendely desktop, google scholar, scopus, ISC, Pubmed, other relevant texts and local books. This review is concerned with characterization of chemical profiles of essential oils, extracts and volatiles, along with relevant biological and phytochemical properties of Ziziphora persica over the 32-year period, 1988–2020. A variety of Eco-phytochemistry and Ethnobotany properties of the Ziziphora persica has been documented, and phytochemicals of the essential oils of this specie has been identified.
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Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Many patients with osteosarcoma readily develop resistance to chemotherapy and have an extremely dismal prognosis. Dioscin, a saponin, is known to exhibit potent anticancer activities and induce cellular death of a variety of cancer types. However, the inhibitory effect of dioscin on osteosarcoma cells and its underlying mechanisms have not been fully elucidated. We investigated the responses of human U2‐OS and MG63 osteosarcoma cells to dioscin with regard to proliferation, apoptosis, migration, and invasion, and studied the effect of dioscin on MAPK‐related proteins by western blot analysis assays. Dioscin inhibited osteosarcoma cell proliferation, migration, and invasion. Moreover, it induced osteosarcoma cell apoptosis via reactive oxygen species (ROS)‐dependent apoptotic signaling. N‐acetylcysteine, a reactive oxygen species inhibitor, suppressed dioscin‐induced apoptosis, indicating that ROS play an essential role in dioscin‐induced apoptosis. Western blot analysis assays showed that p38 MAPK was upregulated after dioscin treatment, and that dioscin induced apoptosis by upregulating ROS‐mediated p38 MAPK signaling. Our study suggests that dioscin possesses antitumor activities against human osteosarcoma cells, inhibits osteosarcoma cell proliferation, migration and invasion, and induces osteosarcoma cell apoptosis through upregulating ROS‐mediated p38 MAPK signaling. This study may provide a new therapeutic strategy and potential clinical applications for the treatment of osteosarcoma.
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Abnormal energy metabolism, as one of the important hallmarks of cancer, was induced by multiple carcinogenic factors and tumor-specific microenvironments. It comprises aerobic glycolysis, de novo lipid biosynthesis, and glutamine-dependent anaplerosis. Considering that metabolic reprogramming provides various nutrients for tumor survival and development, it has been considered a potential target for cancer therapy. Cannabinoids have been shown to exhibit a variety of anticancer activities by unclear mechanisms. This paper first reviews the recent progress of related signaling pathways (reactive oxygen species (ROS), AMP-activated protein kinase (AMPK), mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), hypoxia-inducible factor-1alpha (HIF-1α), and p53) mediating the reprogramming of cancer metabolism (including glucose metabolism, lipid metabolism, and amino acid metabolism). Then we comprehensively explore the latest discoveries and possible mechanisms of the anticancer effects of cannabinoids through the regulation of the above-mentioned related signaling pathways, to provide new targets and insights for cancer prevention and treatment.
Article
Background: Turmeric ( Curcuma longa ) has high potential as a traditional anticancer drug. This study aimed to analyze the anticancer activity of turmeric ethanol extract on T47D cells and examine the interaction of Akt1 protein with compounds contained in turmeric. Methods : The cytotoxicity assay was conducted using WST-1 reagents. Apoptosis assay used annexin V-PI, whereas cell cycle assay used PI, and then the results were analyzed using a flow cytometer. LC-HRMS analysis was conducted to identify the active compounds. Docking between Akt1 and ligands was performed using Autodock 4.2 software. Molecular dynamics simulations were conducted using YASARA with a time parameter of 20 ns, pH 7.4, and 37°C. Results : The extract had a strong toxicity on T47D cells (cytotoxicity IC 50 value: 26.36 ± 1.55 µg/mL). The extract induced apoptosis of T47D cells at the IC 50 dose (~30% cells) and induced the cell cycle arrest in G1 phase. Curcumin, 2-hydroxycinnamic acid and caryophyllene oxide had lower binding energy into Akt1 than AZD5363 used as a positive control. Curcumin, Ar-turmerone, and α-curcumene bind in the ATP binding pocket of Akt1, so the compounds have a high potential to be an ATP-competitive Akt1 inhibitors. The interaction of Akt1 with the compound contained in turmeric had an RMSD backbone value that was more stable than that of ATP and AZD5363. Root-mean-square fluctuation values indicated that amino acid residues that had an essential role in ligand binding sites were stable during simulation. Conclusions: The turmeric ethanol extract had a potential anti-cancer effect by inducing apoptosis and inhibiting cell cycle progression on T47D cells. The docking analysis showed that the active compounds of the extract, such as curcumin, Ar-turmerone, caryophyllene oxide, and α-curcumene, were able to bind into the ATP binding pocket of Akt1 that might inhibit the protein activity and induce cell cycle arrest.
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Clove (Syzygium aromaticum) is one of the most valuable spices that has been widely used for many medicinal purposes and as a food preservative in recent years. The major bioactive compound found both in clove spice and clove essential oil is eugenol (4-all-methoxyphenol C10H12O2) with a ratio of 85%–95%. However, side effects of this alkylphenol on human and animal health have been known for decades. Its cytotoxicity and genotoxicity are the most important factors that limit the consumption of both eugenol and clove by humans. World Health Organization (WHO) specified the acceptable daily intake (ADI) of eugenol which is a maximum of 2.5 mg per kg body weight. Different mechanisms of action have been proposed to explain cytotoxicity of eugenol: (a) oxidation of eugenol by peroxidases generates quinone methide intermediate which is toxic to hepatocytes; (b) high affinity of eugenol to plasma membranes due to its highly lipophilic nature results in cell damage; (c) the influence of eugenol on uncoupling of oxidative phosphorylation in mitochondria; (d) the prooxidant activity of eugenol triggers the formation of oxygen-free radicals that contribute to tissue damage; and (e) protein deactivation and consequently toxicity due to binding of lysine to eugenol. Nevertheless, more detailed in vitro and in vivo studies are still required to clearly reveal the mechanism of action of clove’s toxicity on human health. Toxic effects of spices and their essential oils may occur depending on their areas of use and they are usually dose-dependent.Toxic constituents are generated in three classes as low toxicity compounds, components less harmless than first class, and high toxicity compounds, respectively. This chapter discusses the toxicity of clove spice and eugenol due to their antifungal, antibacterial, and pharmaceutical uses.
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Our current research aims to evaluate the efficiency of a flavor enhancer, maltol (produced by heating ginseng) against cisplatin‐evoked cardiotoxicity by establishing cisplatin‐induced heart injury in vivo and H9C2 rat cardiomyocyte model. The cisplatin‐treated mice at 3 mg/kg for four times on the 7th, 9th, 11th and 13th day, and in them appeared a serious cardiac damage accompanied with the increase in indicators of heart damage. Multiple exposure of 3 mg/kg for four times of cisplatin increased cardiac cells apoptosis with increased expression of Bax and cleaved‐caspase 3, and decreased expression of Bcl‐2. Interestingly, supplement of maltol at doses of 50 and 100 mg/kg for 15 days significantly suppressed the cardiac disturbance. In cultured H9C2 cells, maltol enhanced PI3K/Akt expression level during cisplatin treatment, and reduced cisplatin‐induced apoptosis. Notably, inhibition of PI3K/Akt by LY294002 and HY‐10249A lessened the efficacy of maltol. In mice, maltol apparently induced PI3K/Akt in heart tissues and protected against cisplatin‐induced cardiotoxicity. In conclusion, maltol exerted the protective effects against cisplatin‐induced cardiotoxicity, at least partially by inhibiting the activation of PI3K/Akt signaling pathways in cardiomyocytes, to ease oxidative stress, and alleviate reactive oxygen species‐mediated apoptosis.
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Essential oils obtained from plants play critical roles in food and medicine. In this study, the phytochemical composition of Pulicaria crispa essential oil, and its antibacterial, antioxidant and anticancer properties were determined in vitro. The essential oil was extracted from the aerial parts of P. crispa through hydro-distillation using a Clevenger-type apparatus, and it was analyzed with GC-MS. The most dominant chemical constituents of the essential oil were sesquiterpenes (78.26%). The higher constituents were β-caryophyllene oxide (33.97%), modephene (23.34%), geranyl propionate (6.32%), geranyl isovalerate (6.74%), 4-cadinadiene (5%), humulene (4.05%), and β-caryophyllene (2.73%). The essential oil exhibited DPPH radical activity, and it exerted antibacterial effect against gram positive bacteria (Staphylococcus aureus and methicillin-resistant Staphylococcus aureus. However, it had no antibacterial effect on gram negative bacteria (Pseudomonas aeruginosa, Shigella sonnei, Klebsiella pneumoniae and Escherichia coli). The P. crispa essential oil produced significant cytotoxic effects against Hep-G2, MCF-7, Coca-2, and HT-29 cells. The oil was most toxic to Hep-G2 cells, based on its IC20 and IC50 values. These results indicate that the essential oil from P. crispa has potent biological properties which can be useful in the food and pharmaceutical industries.
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Cancer retains a central place in fatality rates among the wide variety of diseases known world over, and the conventional synthetic medicaments, albeit used until now, produce numerous side effects. As a result, newer, better, and safer alternatives such as natural plant products, are gravely required. Essential oils (EOs) offer a plethora of bioactivities including antibacterial, antiviral, antioxidant, and anticancer properties, therefore, the use of EOs in combination with synthetic drugs or aromatherapy continues to be popular in many settings. In view of the paramount importance of EOs and their potential bioactivities, this review summarizes the current knowledge on the interconnection between EOs and cancer treatment. In particular, the current review presents an updated summary of the chemical composition of EOs, their current applications in cancer treatments based on clinical studies, and the mechanism of action against the cancer cell lines. Similarly, an overview of using EOs in aromatherapy and enhancing immunity during cancer treatment is provided. Further, this review focuses on the recent technological advancements such as the loading of EOs using protein microspheres, ligands, or nanoemulsions/nanoencapsulation, which offer multiple benefits in cancer treatment via site-specific and target-oriented delivery of drugs. The continuing clinical studies of EOs implicate that their pharmacological applications are a rewarding research area.
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Background Saussurea costus Falc with synonymous Aucklandia costus, S. lappa, and Aucklandia lappa, is an ancient perennial plant native to Himalayan region. Purpose S. costus possesses an ethnopharmacological background for treating diarrhea, tenesmus, dyspepsia, vomiting, inflammation, and age-related diseases because it contains many chemical compounds with different biological potentials. Study design in the current study, we investigated the phytochemical constituents of S. costus and its anticancer potential against human colon (HCT116) and hepatic (HepG2) cancer cell lines. Methods In the current study, we identified 122 different chemical compounds using a gas chromatography-mass spectrometry (GC-MS) method and investigated its extract's in vitro anticancer activity. Results Dehydrocostus lactone, β-caryophyllene oxide, anethole, costunolide, β-sitosterol, and γ-bisabolene were recognized by GC-MS to have an anticancer potential as stated in published studies. Vanillosmin, santolinatriene and β-Sitosterol were identified for the first time in costus oil. Therefore, in the current study, S. costus extract induced apoptotic and anti-angiogenic effects against HCT116 and HepG2 cancer cell lines in in vitro and chorioallantoic membrane (CAM) models. Furthermore, S. costus extract has successfully potentiated the anticancer effect of doxorubicin (Dox), the common chemotherapeutic agent for different cancer type treatment. Conclusion We can consider S. costus extract as a promising agent for human colon and hepatic cancers either alone or combined with Dox.
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Cyclophosphamide (CTX) has been broadly used in the clinic for the treatment of autoimmune disorders and ovarian cancer. The process of chemotherapy has significant toxicity in the reproductive system as it has detrimental effects on folliculogenesis, which leads to an irreversible premature ovarian failure (POF). Coenzyme Q10 (CoQ10) has positive impacts on the reproductive system due to its antioxidant properties, protecting the cells from free-radical oxidative damage and apoptosis. However, little is known about the possible synergistic effect of CTX and CoQ10 on the expression of genes involved in folliculogenesis, such as proliferation cell nuclear antigen (PCNA) and follicle-stimulating hormone receptor (FSHR). A total of 32 NMRI mice were applied and divided into four groups, including healthy control, CTX, CTX + CoQ10, and CoQ10 groups. The effects of CoQ10 on CTX-induced ovarian injury and folliculogenesis were examined by histopathological and real-time quantitative reverse transcription-polymerase chain reaction analyses. The rates of fertilization (in vitro fertilization), embryo development, as well as the level of reactive oxygen species (ROS) in metaphase II (MII) mouse oocytes after PMSG/HCC treatment were also assessed. Results showed that the treatment with CTX decreased the mRNA expression of PCNA and FSHR, IVF rate, and embryo development whereas the application of CoQ10 successfully reversed those factors. CoQ10 administration significantly enhanced histological morphology and decreased ROS levels and the number of atretic follicles in the ovary of CTX-treated mice. In conclusion, it seems that the protective effect of CoQ10 is exerted via the antioxidant and proliferative properties of this substance on CTX-induced ovarian damage.
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Background Dysphania ambrosioides (L.) Mosyakin & Clemants is an aromatic herb native to South America, but also distributed widely throughout Africa and Europe. This plant is traditionally used to treat various ailments including, pain and swellings, flu, parasitic diseases, and as analgesic, antipyretic, and wound healing. Phytochemical analyses of D. ambrosioides revealed the presence of terpenoids, flavonoids, coumarins, fatty acids and miscellaneous compounds among others, which might be responsible for its modern pharmacological actions. Objective The present work summarizes recent developments on phytochemistry, ethnomedicinal use, pharmacology, and toxicity of D. ambrosioides. A critical assessment of the literature information of D. ambrosioides is also presented. Methods The available information on D. ambrosioides was collected through libraries and electronic databases [Scifinder, ACS, Scielo, Science direct, Pubmed (National Library of Medicine), Wiley, Springer, PROTA, Web of Science, Google Web, Yahoo search and Google scholar] from respective inception until january 2021. Results More than 150 compounds, including terpenoids, flavonoids, coumarins, fatty acids, and miscellaneous compounds etc.. were identified from D. ambrosioides. D. ambrosioides exhibited a wide range of pharmacological activities, including antimalarial, anti-inflammatory, antiparasitic, anticancer, insecticidal, antigiardial, among others. Metal nanoparticles synthesized from D. ambrosioides extracts presented enhanced pharmacological activities as compared to the crude plant extracts counterparts. Conclusion D. ambrosioides is a promising medicinal plant, however, more in vivo experiments, cytotoxicity tests, and mechanisms of actions of its extracts and compounds are recommended to transubstantiate the ethnomedicinal claims of this plant into scientific rationale-based information.
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Natural sesquiterpenoids caryophyllene and caryophyllene oxide are important resources for organic and medicinal chemistry. Due to their peculiar structure, these sesquiterpenoids can be considered as a universal platform for obtaining compounds of various structures, including biologically active compounds. In this review, we have collected and summarized information on the transformations of caryophyllene and caryophyllene oxide from 1997 to 2020 and considered the issues of their use in organic synthesis to obtain O-, N-, S-derivatives and paid special attention to the use of caryophyllane sesquiterpenoids in the synthesis of natural substances. We hope that this work will be useful to researchers in the field of chemistry of natural compounds and medicinal chemistry, who are engaged in the search and development of new substances with pharmacological activity.Graphic abstract
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Benzyl isothiocyanate (BITC), a dietary cancer chemopreventive agent, causes apoptosis in MDA-MB-231 and MCF-7 human breast cancer cells, but the mechanism of cell death is not fully understood. We now demonstrate that the BITC-induced apoptosis in human breast cancer cells is initiated by reactive oxygen species (ROS) due to inhibition of complex III of the mitochondrial respiratory chain. The BITC-induced ROS production and apoptosis were significantly inhibited by overexpression of catalase and Cu,Zn-superoxide dismutase and pharmacological inhibition of the mitochondrial respiratory chain. The mitochondrial DNA-deficient Rho-0 variant of MDA-MB-231 cells was nearly completely resistant to BITC-mediated ROS generation and apoptosis. The Rho-0 MDA-MB-231 cells also resisted BITC-mediated mitochondrial translocation (activation) of Bax. Biochemical assays revealed inhibition of complex III activity in BITC-treated MDA-MB-231 cells as early as at 1 h of treatment. The BITC treatment caused activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), which function upstream of Bax activation in apoptotic response to various stimuli. Pharmacological inhibition of both JNK and p38 MAPK conferred partial yet significant protection against BITC-induced apoptosis. Activation of JNK and p38 MAPK resulting from BITC exposure was abolished by overexpression of catalase. The BITC-mediated conformational change of Bax was markedly suppressed by ectopic expression of catalytically inactive mutant of JNK kinase 2 (JNKK2(AA)). Interestingly, a normal human mammary epithelial cell line was resistant to BITC-mediated ROS generation, JNK/p38 MAPK activation, and apoptosis. In conclusion, the present study indicates that the BITC-induced apoptosis in human breast cancer cells is initiated by mitochondria-derived ROS.
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The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway mediates the effects of a variety of extracellular signals in a number of cellular processes including cell growth, proliferation, and survival. The alteration of integrants of this pathway through mutation of its coding genes increases the activation status of the signaling and can thus lead to cellular transformation. The frequent dysregulation of the PI3K/Akt pathway in breast cancer (BC) and the mediation of this pathway in different processes characteristically implicated in tumorigenesis have attracted the interest of this pathway in BC; however, a more comprehensive understanding of the signaling intricacies is necessary to develop clinical applications of the modulation of this pathway in this pathology. We review a series of experiments examining the contribution of alteration of integrants of this signaling network to human BC and we make an update of the information about the effect of the modulation of this pathway in this cancer.
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Berberine, an isoquinoline plant alkaloid, has been known to generate a wide variety of biochemical and pharmacological effects. In order to elucidate the molecular mechanism for the berberine-induced enhancement of radio-sensitization, the human hepatoma HepG2 cells were treated with berberine combined with irradiation. The anti-tumor effect of gamma radiation was found to be significantly enhanced by berberine. The evidences of apoptosis, such as apoptotic DNA fragmentation and annexin V staining, were observed in the cells treated with the combination of berberine and irradiation. Additionally, the levels of reactive oxygen species (ROS) and nitric oxide (NO) were apparently elevated in the combination system. The activations of p38, Bax, and caspase-3 were also detected in the irradiated cells pretreated with berberine. The productions of ROS and annexin V staining in the cells treated with the combination of berberine and irradiation were significantly inhibited by the specific inhibitor of p38 MAPK, SB203580. The cell death induced by berberine alone or the combination of berberine and irradiation was suppressed by the anti-oxidant, N-acetyl cysteine (NAC). Taken together, the present results clearly indicate that the combination of berberine and gamma-radiation enhance the anti-cancer effects through the p38 MAPK pathway and ROS generation.
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Mammalian target of rapamycin (mTOR) is a key protein kinase controlling signal transduction from various growth factors and upstream proteins to the level of mRNA and ribosome with a regulatory effect on cell cycle progression, cellular proliferation and growth. TOR genes were discovered rather serendipitously while investigating the cause of resistance to immunosuppressant rapamycin in yeast. In normal cells, mTOR controls brilliantly the load of signals from its effectors resulting in a normal cell function. On the contrary, in various diseases and mainly in cancer this balance is lost due to mutations or overactivation of upstream pathways leading to a persistent proliferation and tumor growth. What makes mTOR attractive to researchers seems to be its key position which is on the crossroad of various signal pathways (Ras, PI3K/Akt, TSC, NF-kappaB) towards mRNA, ribosome, protein synthesis and translation of significant molecules, the uncontrolled production of which may lead to tumor proliferation and growth. Inhibition of mTOR by rapamycin (a natural product) or its analogs aims to prevent the deleterious effects of the abnormal signaling, regardless at which point of the signal pathway has the abnormality launched. Here, we will review the physiological functions of mTOR, its association to carcinogenesis and the latest evidence regarding the use of mTOR inhibitors in cancer treatment as well as future trends and aims of research.
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The relative distribution of androgen (AR), progesterone (PR), and estrogen receptors (ER) was localized and estimated in human prostate tissue by immunohistochemistry in five normal tissue samples, in eight benign hyperplastic (BPH) samples, in nine primary cancers, and in seven prostate cancer metastases. Moreover, three prostatic cancer cell lines (LNCaP, DU 145, and PC 3) were analyzed. A comparison between the results obtained by radioligand binding assays and immunohistochemistry was performed for the AR and PR. Using immunohistochemistry, the AR was exclusively detected in the nuclei of both benign and malignant prostatic epithelial cells. The highest proportion of AR-positive cells was found in BPH and in prostate cancer metastases as compared with normal prostatic tissue. In a majority of the cases, the PR was only present in the nuclei of stromal cells. Benign hyperplastic prostates contained higher proportions of PR-positive cells as compared with primary carcinoma. PR was sparse in epithelial cells. ER-positive stromal cell nuclei were only detected in carcinomatous prostates. A few ER-positive epithelial cell nuclei were found in one sample each of a BPH and normal prostate. All cells from the androgen-dependent, LNCaP, cell line and a majority of the cells from the androgen-independent, DU 145, cell line were AR-positive. In contrast, the cells from the androgen-independent, PC 3, cell line were all AR-negative. All three cell lines were PR- and ER-negative. The radioligand binding technique detected the AR in extracts from both the cytosol and the nucleus. Again BPH contained higher amounts of AR as compared with normal prostatic tissue. The LNCaP cells contained high amounts of cytosolic AR while cells from the DU 145 and PC 3 cell lines lacked detectable AR as estimated by biochemical techniques. There seemed to be a discrepancy between biochemically measured and immunohistochemically estimated receptor content.