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Gadelhaq SM, Aboelhadid SM, Abdel-Baki AAS, Hassan KM, Arafa WM, Ibrahium SM, Al-Quraishy S, Hassan AO, Abd El-Kareem SG. Safety and Efficacy of Pure and a Nanosuspension of D-limonene for Controlling Pigeon Lice. JOURNAL OF MEDICAL ENTOMOLOGY 2023; 60:148-158. [PMID: 36398898 DOI: 10.1093/jme/tjac178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Indexed: 06/16/2023]
Abstract
This study investigated the safety and efficacy of two forms of D-limonene (DL) against Columbicola columbae (pigeon feather lice); pure and a nanoemulsion formulation (DLN). The cell cytotoxicity of the prepared forms of DL/DLN was investigated using skin cell lines. In vitro and ex vivo bioassays were applied on lice. The ex vivo bioassay was done on cut feathers containing lice eggs. The in vivo experiment was conducted on pigeons naturally infested by lice. The infested pigeons were treated with DL, DLN, or deltamethrin (D) as a positive control. Both forms of D-limonene were found to be safe when applied to the normal human skin fibroblast cell line, but DLN was toxic to skin cell carcinoma. The in vitro and ex vivo results of both DL and DLN forms were similar. All eggs treated with DL, DLN, and D failed to hatch (100%). The in vivo results showed complete elimination of lice 24 h post-treatment (PT), and biochemical analysis showed that the treated birds retained normal kidney and liver functions. Treated groups also showed improved productivity in the 4 months PT. In conclusion, DL and DLN are safe and effective in controlling feather lice infestation in pigeons and successful treatment encourages bird productivity.
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Affiliation(s)
- Sahar M Gadelhaq
- Parasitology Department, Faculty of Veterinary Medicine, Minia University, Minia, Egypt
| | - Shawky M Aboelhadid
- Parasitology Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62511, Egypt
| | | | - Khaled M Hassan
- Department of Parasitology, Animal Health Research Institute, Beni-Suef Branch, Egypt
| | - Waleed M Arafa
- Parasitology Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62511, Egypt
| | - Samar M Ibrahium
- Department of Parasitology, Animal Health Research Institute, Fayum Branch, Egypt
| | - Saleh Al-Quraishy
- Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Ahmed O Hassan
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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Anisi Stellati Fructus, a Significant Traditional Chinese Medicine (TCM) Herb and Its Bioactivity against Gastric Cancer. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:4071489. [PMID: 35586683 PMCID: PMC9110155 DOI: 10.1155/2022/4071489] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/21/2022] [Accepted: 03/30/2022] [Indexed: 01/19/2023]
Abstract
Anisi stellati fructus (ASF) is the fruit of Illicium verum Hook F. (Chinese star anise), which is native to many countries, and is a significant Chinese medicinal herb. Gastric cancer (GC) is one of the major fatal types of cancers with multiple stages and a poor prognosis. The present review aims to discuss the bioactive properties of ASF and its phytocompounds against GC, with a particular insight into the molecular mechanisms and signaling pathways involved in its anti-GC mechanism. Furthermore, it highlights the potential mechanism of action of major phytocompounds of ASF against GC. Clinical studies (in vitro and in vivo) regarding the action of ASF and its major bioactive compounds such as quercetin, luteolin, kaempferol, d-limonene, and honokiol against GC were reviewed. For this review, search of literature was performed in Science, PubMed, Google Scholar, Web of Science, and Scopus related to ASF and its phytocompounds, from which only relevant studies were chosen. Major bioactive compounds of ASF and their extracts have proven to be effective against GC due to the mechanistic action of these compounds involving signaling pathways that target cancer cell apoptosis, proliferation, and tumor metastasis in GC cells. Existing reports of these compounds and their combinatory effects with other modern anticancer agents have also been reviewed. From its traditional use to its role as an anticancer agent, ASF and its bioactive phytocompounds have been observed to be effective in modern research, specifically against GC. However, further studies are required for the identification of molecular targets and pharmacokinetic potential and for the formulation of anti-GC drugs.
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Gara-Ali M, Zili F, Hosni K, Ben Ouada H, Ben-Mahrez K. Lipophilic extracts of the thermophilic cyanobacterium Leptolyngbya sp. and chlorophyte Graesiella sp. and their potential use as food and anticancer agents. ALGAL RES 2021. [DOI: 10.1016/j.algal.2021.102511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Hajizadeh MR, Maleki H, Barani M, Fahmidehkar MA, Mahmoodi M, Torkzadeh-Mahani M. In vitro cytotoxicity assay of D-limonene niosomes: an efficient nano-carrier for enhancing solubility of plant-extracted agents. Res Pharm Sci 2019; 14:448-458. [PMID: 31798662 PMCID: PMC6827193 DOI: 10.4103/1735-5362.268206] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The low solubility of the plant-extracted agent like D-limonene in cancer therapy is a critical problem. In this study, we prepared D-limonene-loaded niosomes (D-limonene/Nio) for cancer therapy through in vitro cytotoxicity assay of HepG2, MCF-7, and A549 cell lines. The niosomal formulation was prepared by film hydration technique with Span® 40: Tween® 40: cholesterol (35:35:30 molar ratio) and characterized for vesicle distribution size, morphology, entrapment efficiency (EE%), and in vitro release behaviour. The obtained niosomes showed a nanometric size and spherical morphology with EE% about 87 ± 1.8%. Remarkably prolonged release of D-limonene from niosomes compared to free D-limonene observed. The loaded formulation showed significantly enhanced cytotoxic activity with all three cancer cell lines (HepG2, Macf-7 and A549) at the concentration of 20 μM. These results indicated that niosome loaded with phytochemicals can be a promising nano-carrier for cancer therapy applications.
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Affiliation(s)
- Mohammad Reza Hajizadeh
- Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, I.R. Iran.,Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, I.R. Iran
| | - Haniyeh Maleki
- Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, I.R. Iran.,Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, I.R. Iran
| | - Mahmood Barani
- Department of Chemistry, Shahid Bahonar University of Kerman, Kerman, I.R. Iran
| | - Mohammad Ali Fahmidehkar
- Research Center of Advanced Technologies in Medicine, Torbat Heydariyeh University of Medical Sciences, Ttorbat Heydariyeh, I.R. Iran
| | - Mehdi Mahmoodi
- Department of Clinical Biochemistry, Afzalipoor Faculty of Medicine, Kerman University of Medical Sciences, Kerman, I.R. Iran
| | - Masoud Torkzadeh-Mahani
- Department of Biotechnology, Institute of Science, High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman, I.R. Iran
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Protective Effect of Boswellic Acids against Doxorubicin-Induced Hepatotoxicity: Impact on Nrf2/HO-1 Defense Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018. [PMID: 29541348 PMCID: PMC5818967 DOI: 10.1155/2018/8296451] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The current study aimed to investigate the potential protective role of boswellic acids (BAs) against doxorubicin- (DOX-) induced hepatotoxicity. Also, the possible mechanisms underlying this protection; antioxidant, as well as the modulatory effect on the Nrf2 transcription factor/hem oxygenase-1 (Nrf2/HO-1) pathway in liver tissues, was investigated. Animals were allocated to five groups: group 1: the saline control, group 2: the DOX group, animals received DOX (6 mg/kg, i.p.) weekly for a period of three weeks, and groups 3–5: animals received DOX (6 mg/kg, i.p.) weekly and received protective doses of BAs (125, 250, and 500 mg/kg/day). Treatment with BAs significantly improved the altered liver enzyme activities and oxidative stress markers. This was coupled with significant improvement in liver histopathological features. BAs increased the Nrf2 and HO-1 expression, which provided protection against DOX-induced oxidative insult. The present results demonstrated that BAs appear to scavenge ROS and inhibit lipid peroxidation and DNA damage of DOX-induced hepatotoxicity. The antioxidant efficacy of BAs might arise from its modulation of the Nrf2/HO-1 pathway and thereby protected liver from DOX-induced oxidative injury.
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Abstract
Liver cancer remains one of the most common human cancers with a high mortality rate. Therapies for hepatocellular carcinoma (HCC) remain ineffective, due to the heterogeneity of HCC with regard to both the etiology and mutation spectrum, as well as its chemotherapy resistant nature; thus surgical resection and liver transplantation remain the gold standard of patient care. The most common etiologies of HCC are extrinsic factors. Humans have multiple defense mechanisms against extrinsic factor-induced carcinogenesis, of which tumor suppressors play crucial roles in preventing normal cells from becoming cancerous. The tumor suppressor p53 is one of the most frequently mutated genes in liver cancer. p53 regulates expression of genes involved in cell cycle progression, cell death, and cellular metabolism to avert tumor development due to carcinogens. This review article mainly summarizes extrinsic factors that induce liver cancer and potentially have etiological association with p53, including aflatoxin B1, vinyl chloride, non-alcoholic fatty liver disease, iron overload, and infection of hepatitis viruses.
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Affiliation(s)
- Tim Link
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Tomoo Iwakuma
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Cho KS, Lim YR, Lee K, Lee J, Lee JH, Lee IS. Terpenes from Forests and Human Health. Toxicol Res 2017; 33:97-106. [PMID: 28443180 PMCID: PMC5402865 DOI: 10.5487/tr.2017.33.2.097] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 02/14/2017] [Accepted: 02/16/2017] [Indexed: 12/18/2022] Open
Abstract
Forest bathing has beneficial effects on human health via showering of forest aerosols as well as physical relaxation. Terpenes that consist of multiple isoprene units are the largest class of organic compounds produced by various plants, and one of the major components of forest aerosols. Traditionally, terpene-containing plant oil has been used to treat various diseases without knowing the exact functions or the mechanisms of action of the individual bioactive compounds. This review categorizes various terpenes easily obtained from forests according to their anti-inflammatory, anti-tumorigenic, or neuroprotective activities. Moreover, potential action mechanisms of the individual terpenes and their effects on such processes, which are described in various in vivo and in vitro systems, are discussed. In conclusion, the studies that show the biological effectiveness of terpenes support the benefits of forest bathing and propose a potential use of terpenes as chemotherapeutic agents for treating various human diseases.
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Affiliation(s)
- Kyoung Sang Cho
- Department of Biological Sciences, Konkuk University, Seoul, Korea.,Research Center for Coupled Human and Natural Systems for Ecowelfare, Konkuk University, Seoul, Korea
| | - Young-Ran Lim
- Department of Biological Sciences, Konkuk University, Seoul, Korea
| | - Kyungho Lee
- Department of Biological Sciences, Konkuk University, Seoul, Korea.,Research Center for Coupled Human and Natural Systems for Ecowelfare, Konkuk University, Seoul, Korea
| | - Jaeseok Lee
- Department of Biological Sciences, Konkuk University, Seoul, Korea.,Research Center for Coupled Human and Natural Systems for Ecowelfare, Konkuk University, Seoul, Korea
| | - Jang Ho Lee
- Department of Biological Sciences, Konkuk University, Seoul, Korea
| | - Im-Soon Lee
- Department of Biological Sciences, Konkuk University, Seoul, Korea.,Research Center for Coupled Human and Natural Systems for Ecowelfare, Konkuk University, Seoul, Korea
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8
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Therapeutic properties of green tea against environmental insults. J Nutr Biochem 2016; 40:1-13. [PMID: 27723473 DOI: 10.1016/j.jnutbio.2016.05.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 05/04/2016] [Accepted: 05/06/2016] [Indexed: 12/23/2022]
Abstract
Pesticides, smoke, mycotoxins, polychlorinated biphenyls (PCBs), and arsenic are the most common environmental toxins and toxicants to humans. These toxins and toxicants may impact on human health at the molecular (DNA, RNA, or protein), organelle (mitochondria, lysosome, or membranes), cellular (growth inhibition or cell death), tissue, organ, and systemic levels. Formation of reactive radicals, lipid peroxidation, inflammation, genotoxicity, hepatotoxicity, embryotoxicity, neurological alterations, apoptosis, and carcinogenic events are some of the mechanisms mediating the toxic effects of the environmental toxins and toxicants. Green tea, the nonoxidized and nonfermented form of tea that contains several polyphenols, including green tea catechins, exhibits protective effects against these environmental toxins and toxicants in preclinical studies and to a much-limited extent, in clinical trials. The protective effects are collectively mediated by antioxidant, antiinflammatory, antimutagenic, hepatoprotective and neuroprotective, and anticarcinogenic activities. In addition, green tea modulates signaling pathway including NF-κB and ERK pathways, preserves mitochondrial membrane potential, inhibits caspase-3 activity, down-regulates proapoptotic proteins, and induces the phase II detoxifying pathway. The bioavailability and metabolism of green tea and its protective effects against environmental insults induced by pesticides, smoke, mycotoxins, PCBs, and arsenic are reviewed in this paper. Future studies with emphasis on clinical trials should identify biomarkers of green tea intake, examine the mechanisms of action of green tea polyphenols, and investigate potential interactions of green tea with other toxicant-modulating dietary factors.
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Tagaram HRS, Desai D, Li G, Liu D, Rountree CB, Gowda K, Berg A, Amin S, Staveley-O'Carroll KF, Kimchi ET. A Selenium Containing Inhibitor for the Treatment of Hepatocellular Cancer. Pharmaceuticals (Basel) 2016; 9:E18. [PMID: 27023566 PMCID: PMC4932536 DOI: 10.3390/ph9020018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 03/11/2016] [Accepted: 03/16/2016] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most deadly cancer in the world. New treatment strategies are desperately needed due to limited standard therapies. Activation of the Erk, Akt, and STAT3pathways is implicated in the prognosis of HCC. The Se,Se'-1,4-phenylenebis(1,2-ethanediyl) bisisoselenourea (PBISe), is a selenium-containing MAPK and PI3 kinase inhibitor, effectively inhibit tumorigenesis in a variety of experimental models. The aim of our study is to demonstrate the potential role of PBISe in the treatment of HCC. The anti-proliferative and pro-apoptotic ability of PBISe is studied in vitro in four human HCC cell lines and in vivo in a spontaneous murine HCC model. Inhibition of cancer growth was performed by cell viability assay and apoptosis by caspase 3/7, PARP cleavage, annexin-V, and TUNEL assays. Role of PBISe on PI3 kinase, MAPK and STAT3 signaling is determined by Western blotting. In vivo effects of PBISe on tumor sizes were monitored using MRI in a spontaneous murine HCC. Liver tissues from the PBISe-treated mice are analyzed for angiogenesis, proliferation, and signaling pathway markers. Overall, PBISe activated caspase-3/7 and increased DNA fragmentation, which is positively correlated with the increased PARP cleavage. PBISe promoted apoptosis by inhibiting PI3K, MAPK, and STAT3 signaling with significant reduction in the tumor sizes (p < 0.007). PBISe-treated tumors reduced survival marker PCNA, and angiogenesis markers Vegf-A, Vegf-R3 and CD34. These results demonstrate the chemotherapeutic effects of PBISe, by inhibiting tumor growth and facilitating tumor apoptosis for HCC treatment.
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Affiliation(s)
| | - Dhimant Desai
- Department of Pharmacology, Pennsylvania State University, Hershey, PA 17033, USA.
| | - Guangfu Li
- Medical University of South Carolina, Charleston, SC 29425, USA.
| | - Dai Liu
- Medical University of South Carolina, Charleston, SC 29425, USA.
| | - C Bart Rountree
- Bon Secours Pediatric Associates, 5875 Bremo Road, Richmond, VA 23226, USA.
| | - Kavitha Gowda
- Department of Surgery, Pennsylvania State University, Hershey, PA 17033, USA.
| | - Arthur Berg
- Department of Public Health Sciences, Pennsylvania State University, Hershey, PA 17033, USA.
| | - Shantu Amin
- Department of Pharmacology, Pennsylvania State University, Hershey, PA 17033, USA
| | | | - Eric T Kimchi
- Medical University of South Carolina, Charleston, SC 29425, USA.
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Chueca B, Pagán R, García-Gonzalo D. Differential mechanism of Escherichia coli Inactivation by (+)-limonene as a function of cell physiological state and drug's concentration. PLoS One 2014; 9:e94072. [PMID: 24705541 PMCID: PMC3976388 DOI: 10.1371/journal.pone.0094072] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 03/10/2014] [Indexed: 11/18/2022] Open
Abstract
(+)-limonene is a lipophilic antimicrobial compound, extracted from citrus fruits' essential oils, that is used as a flavouring agent and organic solvent by the food industry. A recent study has proposed a common and controversial mechanism of cell death for bactericidal antibiotics, in which hydroxyl radicals ultimately inactivated cells. Our objective was to determine whether the mechanism of Escherichia coli MG1655 inactivation by (+)-limonene follows that of bactericidal antibiotics. A treatment with 2,000 μL/L (+)-limonene inactivated 4 log10 cycles of exponentially growing E. coli cells in 3 hours. On one hand, an increase of cell survival in the ΔacnB mutant (deficient in a TCA cycle enzyme), or in the presence of 2,2′-dipyridyl (inhibitor of Fenton reaction by iron chelation), thiourea, or cysteamine (hydroxyl radical scavengers) was observed. Moreover, the ΔrecA mutant (deficient in an enzyme involved in SOS response to DNA damage) was more sensitive to (+)-limonene. Thus, this indirect evidence indicates that the mechanism of exponentially growing E. coli cells inactivation by 2,000 μL/L (+)-limonene is due to the TCA cycle and Fenton-mediated hydroxyl radical formation that caused oxidative DNA damage, as observed for bactericidal drugs. However, several differences have been observed between the proposed mechanism for bactericidal drugs and for (+)-limonene. In this regard, our results demonstrated that E. coli inactivation was influenced by its physiological state and the drug's concentration: experiments with stationary-phase cells or 4,000 μL/L (+)-limonene uncovered a different mechanism of cell death, likely unrelated to hydroxyl radicals. Our research has also shown that drug's concentration is an important factor influencing the mechanism of bacterial inactivation by antibiotics, such as kanamycin. These results might help in improving and spreading the use of (+)-limonene as an antimicrobial compound, and in clarifying the controversy about the mechanism of inactivation by bactericidal antibiotics.
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Affiliation(s)
- Beatriz Chueca
- Tecnología de los Alimentos, Departamento de Producción Animal y Ciencia de los Alimentos, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
| | - Rafael Pagán
- Tecnología de los Alimentos, Departamento de Producción Animal y Ciencia de los Alimentos, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
| | - Diego García-Gonzalo
- Tecnología de los Alimentos, Departamento de Producción Animal y Ciencia de los Alimentos, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
- * E-mail:
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Shojaei S, Kiumarsi A, Moghadam AR, Alizadeh J, Marzban H, Ghavami S. Perillyl Alcohol (Monoterpene Alcohol), Limonene. Enzymes 2014; 36:7-32. [PMID: 27102697 DOI: 10.1016/b978-0-12-802215-3.00002-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Natural products have a long history of use in traditional medicines and their activities against different diseases have been the focus of many basic and clinical researches in past few decades. The essential oils, volatile liquid containing aroma compound from plants, are known as active ingredients in the herbal medicine. Perillyl alcohol (POH) is usually available through dietary sources and is being explored for its cancer chemoprevention, tumor growth suppression, and regression. Citrus peels are the waste product of juice manufacturing industries and have been considered as a critical problem for environmental green ecology policies for years. One of the most well-known approaches to overcome this problem is transformation of these monoterpene by the use of specific strains of bacteria or yeasts. Limonene (1-methyl-4-isopropyl-cyclohexene) is a monoterpene, as other monoterpenes consists of two isoprene units, that comprises more than 90% of citrus essential oil and it exists in many fruits and vegetables. Although, the anticancer activity of d-limonene has identified nearly two decades ago, it has recently attracted much more attention in translational medicine. In this chapter, we will overview the anticancer effects of POH and d-limonene. Later, we will address the pharmacokinetics of these compounds, highlight the signaling pathways which are targeted by these proteins, review the clinical trials which have been done for these compounds in different cancer models, and finally discuss the future directions of the research in this field that might be more applicable in future cancer therapy strategies.
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Affiliation(s)
- Shahla Shojaei
- Department of Biochemistry, Recombinant Protein Laboratory, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Kiumarsi
- Chang School of Continuing Education, Ryerson University, Toronto, Ontario, Canada
| | - Adel Rezaei Moghadam
- Faculty of Veterinary Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Javad Alizadeh
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Hassan Marzban
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada; Health Policy Research Centre, Shiraz University of Medical Science, Shiraz, Iran.
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Mauro M, Catanzaro I, Naselli F, Sciandrello G, Caradonna F. Abnormal mitotic spindle assembly and cytokinesis induced by D-Limonene in cultured mammalian cells. Mutagenesis 2013; 28:631-5. [PMID: 23913329 DOI: 10.1093/mutage/get040] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
D-Limonene is found widely in citrus and many other plant species; it is a major constituent of many essential oils and is used as a solvent for commercial purposes. With the discovery of its chemotherapeutic properties against cancer, it is important to investigate the biological effects of the exposure to D-Limonene and elucidate its, as yet unknown, mechanism of action. We reported here that D-Limonene is toxic in V79 Chinese hamster cells in a dose-dependent manner. Moreover, to determine the cellular target of D-Limonene, we performed morphological observations and immunocytochemical analysis and we showed that this drug has a direct effect on dividing cells preventing assembly of mitotic spindle microtubules. This affects both chromosome segregation and cytokinesis, resulting in aneuploidy that in turn can lead to cell death or genomic instability.
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Affiliation(s)
- Maurizio Mauro
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche ( STEBICEF, sezione di Biologia Cellulare) Università di Palermo, Viale delle Scienze, Edificio 16, 90128 Palermo, Italy
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Piaru SP, Perumal S, Cai LW, Mahmud R, Majid AMSA, Ismail S, Man CN. Chemical composition, anti-angiogenic and cytotoxicity activities of the essential oils ofCymbopogan citratus(lemon grass) against colorectal and breast carcinoma cell lines. JOURNAL OF ESSENTIAL OIL RESEARCH 2012. [DOI: 10.1080/10412905.2012.703496] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Potential chemopreventive role of chrysin against N-nitrosodiethylamine-induced hepatocellular carcinoma in rats. ACTA ACUST UNITED AC 2012. [DOI: 10.1016/j.bionut.2011.06.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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15
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McQuistan TJ, Simonich MT, Pratt MM, Pereira CB, Hendricks JD, Dashwood RH, Williams DE, Bailey GS. Cancer chemoprevention by dietary chlorophylls: a 12,000-animal dose-dose matrix biomarker and tumor study. Food Chem Toxicol 2012; 50:341-52. [PMID: 22079312 PMCID: PMC3486520 DOI: 10.1016/j.fct.2011.10.065] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 10/14/2011] [Accepted: 10/19/2011] [Indexed: 02/02/2023]
Abstract
Recent pilot studies found natural chlorophyll (Chl) to inhibit carcinogen uptake and tumorigenesis in rodent and fish models, and to alter uptake and biodistribution of trace (14)C-aflatoxin B1 in human volunteers. The present study extends these promising findings, using a dose-dose matrix design to examine Chl-mediated effects on dibenzo(def,p)chrysene (DBC)-induced DNA adduct formation, tumor incidence, tumor multiplicity, and changes in gene regulation in the trout. The dose-dose matrix design employed an initial 12,360 rainbow trout, which were treated with 0-4000ppm dietary Chl along with 0-225ppm DBC for up to 4weeks. Dietary DBC was found to induce dose-responsive changes in gene expression that were abolished by Chl co-treatment, whereas Chl alone had no effect on the same genes. Chl co-treatment provided a dose-responsive reduction in total DBC-DNA adducts without altering relative adduct intensities along the chromatographic profile. In animals receiving DBC alone, liver tumor incidence (as logit) and tumor multiplicity were linear in DBC dose (as log) up to their maximum-effect dose, and declined thereafter. Chl co-treatment substantially inhibited incidence and multiplicity at DBC doses up to their maximum-effect dose. These results show that Chl concentrations encountered in Chl-rich green vegetables can provide substantial cancer chemoprotection, and suggest that they do so by reducing carcinogen bioavailability. However, at DBC doses above the optima, Chl co-treatments failed to inhibit tumor incidence and significantly enhanced multiplicity. This finding questions the human relevance of chemoprevention studies carried out at high carcinogen doses that are not proven to lie within a linear, or at least monotonic, endpoint dose-response range.
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Affiliation(s)
- Tammie J McQuistan
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
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Kuttan G, Pratheeshkumar P, Manu KA, Kuttan R. Inhibition of tumor progression by naturally occurring terpenoids. PHARMACEUTICAL BIOLOGY 2011; 49:995-1007. [PMID: 21936626 DOI: 10.3109/13880209.2011.559476] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
CONTEXT Cancer is a major public health problem in India and many other parts of the world. Its two main characteristics are uncontrolled cell growth and metastasis. Natural products represent a rich source of compounds that have found many applications in various fields of medicines and therapy including cancer therapy. Effective ingredients in several plant-derived medicinal extracts are terpenoid compounds and many terpenes have biological activities and are used for the treatment of human diseases. OBJECTIVES This review attempted to collect all available published scientific literature of eight naturally occurring terpenoids and their effect on inhibition of tumor progression. METHODS The present review is about eight potent naturally occurring terpenoids that have been studied for their pharmacological properties in our lab and this review includes 130 references compiled from all major databases. RESULTS Literature survey revealed that triterpenoids, such as glycyrrhizic acid, ursolic acid, oleanolic acid, and nomilin, the diterpene andrographolide, and the monoterpenoids like limonene and perillic acid had shown immunomodulatory and antitumor activities. All of them could induce apoptosis in various cancer cells by activating various proapoptotic signaling cascades. Many of these terpenoids found to inhibit metastatic progression and tumor-induced angiogenesis. The molecular mechanisms that involved in these activities include inhibition of various oncogenic and anti-apoptotic signaling pathways and suppression or nuclear translocation of various transcription factors including nuclear factor kappa B (NF-κB). CONCLUSION The chemopreventive and chemoprotective effects of these compounds point toward their possible role in modern anticancer therapies.
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Affiliation(s)
- Girija Kuttan
- Department of Immunology, Amala Cancer Research Centre, Amala Nagar, Thrissur, Kerala, India.
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Shcherbina Y, Roth Z, Nussinovitch A. Physical properties of gum karaya-starch-essential oil patches. AAPS PharmSciTech 2010; 11:1276-86. [PMID: 20711695 DOI: 10.1208/s12249-010-9502-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2010] [Accepted: 07/23/2010] [Indexed: 11/30/2022] Open
Abstract
Essential oils are used in foods, cosmetics, and pharmaceuticals. Despite the recent marketing of novel essential-oil-containing patches, there is no information on their production, constituents, or physical properties. The objectives of this study were to produce essential-oil patches and characterize their physical properties. The essential oil of Lavandula angustifolia (lavender) was included at concentrations of 2.5% to 10% in patches manufactured from the exudate gum karaya, propylene glycol, glycerol, emulsifier, and optionally, potato starch as filler. Inclusion of essential oil reduced patch strength, stiffness, and elasticity relative to patches without essential oil. Inclusion of starch in the essential-oil patches strengthened them, but reduced their elasticity. Patches' adhesion to substrate was examined by both peeling and probe-tack tests: the higher the inclusion of essential oils within the patch, the larger the decrease in its adhesion to substrate. Addition of starch to essential-oil-containing patches increased their adhesion relative to their essential-oil-only counterparts. Scanning electron micrographs of the patches provided evidence of entrapped starch granules. Although inclusion of essential oil reduced both the mechanical properties and adhesion of the patches, a high proportion of essential oil can still be included without losing patch integrity or eliminating its adhesiveness to the skin.
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Holland R, Navamal M, Velayutham M, Zweier JL, Kensler TW, Fishbein JC. Hydrogen peroxide is a second messenger in phase 2 enzyme induction by cancer chemopreventive dithiolethiones. Chem Res Toxicol 2010; 22:1427-34. [PMID: 19785463 DOI: 10.1021/tx900110n] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The ability of three dithiolethione cancer chemopreventives, oltipraz 1, anetholedithione (ADT) 2, 1,2-dithiole-3-thione (D3T) 3, and the major metabolite, 4, of 1, to induce the cytoprotective enzyme NQO1 in Hepa 1c1c7 cells and the inhibition of this induction by catalase are demonstrated. The ability of 1, 3, and 4 to form O(2)(*) has been reported, and it is here demonstrated that 2 decomposes in the presence of GSH to form, upon addition of the nitrone spin trap DMPO, the DMPO-OH adduct that is detectable by EPR. Decomposition of 2 in the presence of GSH elicits, upon the addition of hydroethidine and excitation at 510 nm, fluorescence at 580 nm that is diminished by the addition of superoxide dismutase. The compound 4, is a product of the reduction of 1, and it is demonstrated that 2 and 3 decompose in the presence of reductants such as thiolates and NaBH(4), followed by addition of CH(3)I, to form the dimethylated products of reductive cleavage of the S(1)-S(2) bond. The same products are isolated subsequent to lysis in buffer containing CH(3)I of Hepa 1c1c7 cells treated with 2 or 3. Reductive cleavage of 2 and 3 in aqueous ethanol by NaBH(4) in an argon atmosphere, followed by acidic destruction of remaining borohydride and neutralization and introduction of O(2) results in the reformation of 2 and 3 to the extent of 80 and 33%, respectively. The data in toto are consistent with a model in which dithiolethiones, generally, undergo reductive cleavage in Hepa 1c1c7 cells, thereby resulting in the generation of O(2)(*) that dismutates to H(2)O(2), that subsequently, by direct or indirect means, effects the nuclear translocation of transcription factor Nrf2, that upregulates phase 2 enzyme expression.
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Affiliation(s)
- Ryan Holland
- Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250, USA. CA91032
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González-Molina E, Domínguez-Perles R, Moreno DA, García-Viguera C. Natural bioactive compounds of Citrus limon for food and health. J Pharm Biomed Anal 2009; 51:327-45. [PMID: 19748198 DOI: 10.1016/j.jpba.2009.07.027] [Citation(s) in RCA: 245] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2009] [Revised: 06/19/2009] [Accepted: 07/22/2009] [Indexed: 12/25/2022]
Abstract
Citrus genus is the most important fruit tree crop in the world and lemon is the third most important Citrus species. Several studies highlighted lemon as an important health-promoting fruit rich in phenolic compounds as well as vitamins, minerals, dietary fiber, essential oils and carotenoids. Lemon fruit has a strong commercial value for the fresh products market and food industry. Moreover, lemon productive networks generate high amounts of wastes and by-products that constitute an important source of bioactive compounds with potential for animal feed, manufactured foods, and health care. This review focuses on the phytochemistry and the analytical aspects of lemon compounds as well as on the importance for food industry and the relevance of Citrus limon for nutrition and health, bringing an overview of what is published on the bioactive compounds of this fruit.
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Affiliation(s)
- E González-Molina
- Lab Fitoquímica, Dept Ciéncia y Tecnología de los Alimentos, CEBAS-CSIC, Apdo 164, 30100, Espinardo, Murcia, Spain
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20
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Kang KW. This month in APR. Arch Pharm Res 2009; 32:463-4. [PMID: 19407961 DOI: 10.1007/s12272-009-0002-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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21
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Lee CY, Hsu YC, Wang JY, Chen CC, Chiu JH. Chemopreventive effect of selenium and Chinese medicinal herbs on N-nitrosobis(2-oxopropyl)amine-induced hepatocellular carcinoma in Syrian hamsters. Liver Int 2008; 28:841-55. [PMID: 18346132 PMCID: PMC2440552 DOI: 10.1111/j.1478-3231.2008.01698.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND/AIMS Oxidative DNA damage by reactive oxygen species is involved in the process of liver carcinogenesis. To test the hypothesis that a remedy containing Scutellaria baicalensis Georgi (Sb) and Bupleurum scorzonerifolfium Willd (Bs) (Sb/Bs remedy) modulates hepatic neoplastic growth, BOP (N-nitrosobis(2-oxopropyl)amine)-induced liver cancers in hamsters were established. METHODS Parameters such as survival rate, tumour area, tumour foci, 8-hydroxydeoxyguanosine (8-OHdG), caspase-3, transforming growth factor (TGF-beta1) and tumour necrosis factor-alpha (TNF-alpha) were measured after Sb/Bs remedy treatment during BOP-induced carcinogenesis. RESULTS The results showed that the Sb/Bs remedy and its constituents Sb and Bs suppressed the tumour area in BOP-induced liver tumours. Because selenium (Sel) is toxic at a high dose (10 mg/kg), with a low survival rate (0%), the combination of Sb/Bs remedy and low-dose Sel (1 mg/kg) was found to decrease the tumour area and the number of tumour foci while increasing serum TNF-alpha and TGF-beta1, but not IL-6 levels. Besides, the Sb/Bs remedy, when combined with low-dose Sel, not only decreased the expression of 8-OHdG and increased caspase-3 expression within the glutathione S-transferase placental form-positive tumour foci but also increased tumour apoptosis in BOP-induced hamsters. CONCLUSIONS We conclude that low-dose Sel has a chemoprevention effect on BOP-induced liver tumours and such an effect was more enhanced when combined with Sb/Bs treatment.
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Affiliation(s)
- Chang-Yin Lee
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming UniversityTaipei, Taiwan, Republic of China
| | - Yi-Chao Hsu
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming UniversityTaipei, Taiwan, Republic of China
| | - Jir-You Wang
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming UniversityTaipei, Taiwan, Republic of China
| | - Chien-Chih Chen
- National Research Institute of Chinese MedicineTaipei, Taiwan, Republic of China
| | - Jen-Hwey Chiu
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming UniversityTaipei, Taiwan, Republic of China,Cheng-Hsiung Rehabilitation Medical CenterTaipei, Taiwan, Republic of China,Division of General Surgery, Department of Surgery, Veterans General HospitalTaipei, Taiwan, Republic of China
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Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection is a significant public health problem, with a worldwide prevalence of approximately 170 million. The standard of care for chronic HCV, a combination of alpha-interferon (IFN) and ribavirin, is only 50% effective, has serious side effects, and can be prohibitively expensive for low-income countries with a high prevalence of HCV. Many patients use natural products, including those who are not eligible for IFN/ribavirin, cannot afford treatment, or fail to respond to IFN. METHODS Extensive literature searches were conducted in order to identify clinical trials and reviews of natural products used for treatment of chronic HCV. This review focuses on the composition, pharmacology and results of clinical trials of three natural products: Oxymatrine, TJ-108/schisandra/Gomisin A and lactoferrin. RESULTS Several laboratory and human studies have been performed to evalaute these alternative treatments, but many of these studies are small, uncontrolled and have other important design flaws. While they do offer some safety and efficacy data, none of these studies is conclusive. CONCLUSION Further research is needed on the effectiveness of these natural products for treatment of chronic HCV, including their preparation and standardization.
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Affiliation(s)
- H S Azzam
- Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD 21201-1596, USA.
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Edris AE. Pharmaceutical and therapeutic Potentials of essential oils and their individual volatile constituents: a review. Phytother Res 2007; 21:308-23. [PMID: 17199238 DOI: 10.1002/ptr.2072] [Citation(s) in RCA: 631] [Impact Index Per Article: 35.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Essential oils and their volatile constituents are used widely to prevent and treat human disease. The possible role and mode of action of these natural products is discussed with regard to the prevention and treatment of cancer, cardiovascular diseases including atherosclerosis and thrombosis, as well as their bioactivity as antibacterial, antiviral, antioxidants and antidiabetic agents. Their application as natural skin penetration enhancers for transdermal drug delivery and the therapeutic properties of essential oils in aroma and massage therapy will also be outlined.
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Affiliation(s)
- Amr E Edris
- Aroma and Flavor Chemistry Department, National Research Center, Dokki, El Behose Street, Dokki, 12622, Cairo, Egypt.
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Aouacheria A, Navratil V, Barthelaix A, Mouchiroud D, Gautier C. Bioinformatic screening of human ESTs for differentially expressed genes in normal and tumor tissues. BMC Genomics 2006; 7:94. [PMID: 16640784 PMCID: PMC1459866 DOI: 10.1186/1471-2164-7-94] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2005] [Accepted: 04/26/2006] [Indexed: 11/24/2022] Open
Abstract
Background Owing to the explosion of information generated by human genomics, analysis of publicly available databases can help identify potential candidate genes relevant to the cancerous phenotype. The aim of this study was to scan for such genes by whole-genome in silico subtraction using Expressed Sequence Tag (EST) data. Methods Genes differentially expressed in normal versus tumor tissues were identified using a computer-based differential display strategy. Bcl-xL, an anti-apoptotic member of the Bcl-2 family, was selected for confirmation by western blot analysis. Results Our genome-wide expression analysis identified a set of genes whose differential expression may be attributed to the genetic alterations associated with tumor formation and malignant growth. We propose complete lists of genes that may serve as targets for projects seeking novel candidates for cancer diagnosis and therapy. Our validation result showed increased protein levels of Bcl-xL in two different liver cancer specimens compared to normal liver. Notably, our EST-based data mining procedure indicated that most of the changes in gene expression observed in cancer cells corresponded to gene inactivation patterns. Chromosomes and chromosomal regions most frequently associated with aberrant expression changes in cancer libraries were also determined. Conclusion Through the description of several candidates (including genes encoding extracellular matrix and ribosomal components, cytoskeletal proteins, apoptotic regulators, and novel tissue-specific biomarkers), our study illustrates the utility of in silico transcriptomics to identify tumor cell signatures, tumor-related genes and chromosomal regions frequently associated with aberrant expression in cancer.
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Affiliation(s)
- Abdel Aouacheria
- Laboratoire de Biométrie et Biologie Evolutive, CNRS UMR 5558, Université Claude Bernard Lyon 1, 69622 Villeurbanne Cedex, France
- Current address: Apoptosis and Oncogenesis Laboratory, IBCP, UMR 5086 CNRS-UCBL, IFR 128, Lyon, France
| | - Vincent Navratil
- Laboratoire de Biométrie et Biologie Evolutive, CNRS UMR 5558, Université Claude Bernard Lyon 1, 69622 Villeurbanne Cedex, France
| | | | - Dominique Mouchiroud
- Laboratoire de Biométrie et Biologie Evolutive, CNRS UMR 5558, Université Claude Bernard Lyon 1, 69622 Villeurbanne Cedex, France
| | - Christian Gautier
- Laboratoire de Biométrie et Biologie Evolutive, CNRS UMR 5558, Université Claude Bernard Lyon 1, 69622 Villeurbanne Cedex, France
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Huetz P, Mavaddat N, Mavri J. Reaction between Ellagic Acid and an Ultimate Carcinogen. J Chem Inf Model 2005; 45:1564-70. [PMID: 16309255 DOI: 10.1021/ci050163c] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The reaction coordinate between a typical ultimate carcinogen benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) and ellagic acid, a proven chemopreventive agent active against cancers caused by polycyclic aromatic hydrocarbons (PAHs), was examined by density functional theory (DFT) and semiempirical MO calculations, and activation energy was calculated. The effect of a polar environment was included using Tomasi and the Langevin dipoles methods. The calculated BPDE/ellagic acid reaction free energy of activation is found to be in decent agreement with experimental data [Sayer, J. M. et al. J. Am. Chem. Soc. 1982, 104, 5562-5564]. This work sheds light on the mechanism of action of ellagic acid. Quantum chemical calculations of this kind are valuable for the design of ellagic acid derivatives with even lower activation energy and increased reactivity toward ultimate carcinogens as well as controlled reactivity toward DNA.
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Affiliation(s)
- Philippe Huetz
- Laboratoire de Physique Moléculaire, UMR CNRS 6624, Faculté des Sciences et Techniques, La Bouloie, Université de Franche-Comté, 25030 Besançon Cedex, France
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Di Bisceglie AM, Osmack P, Brunt EM. Chemoprevention of hepatocellular carcinoma: Use of tamoxifen in an animal model of hepatocarcinogenesis. ACTA ACUST UNITED AC 2005; 145:134-8. [PMID: 15871304 DOI: 10.1016/j.lab.2005.01.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Hepatocellular carcinoma (HCC) is common worldwide and growing in importance in the West. HCC often occurs against a background of liver disease, tends to present at an advanced stage, and has a poor prognosis, suggesting that it is an ideal target for chemoprevention. We sought to identify in an animal model chemopreventive agents for HCC that might be tested in human subjects. To this end, we induced liver tumors by injecting ethyl-nitrosourea in 6-week-old male B6C3F1 mice. Two chemopreventive agents were administered over a period of 60 weeks: tamoxifen (420 mg/kg feed) and a retinoid, 13-cis-retinoic acid (200 mg/kg feed). Animals were killed at 60 weeks and their livers examined for HCC and premalignant lesions. All liver lesions (altered foci, adenomata, HCC) occurred significantly less frequently in the tamoxifen-treated group than the group given only ethylnitrosourea (HCC developed in 2 of 47 (4%) vs 11 of 44 (25%); P < .001). On the other hand, retinoic acid appeared to increase the number of liver tumors, and in 2 animals angiosarcoma developed. Tamoxifen significantly decreased the incidence of chemical hepatocarcinogenesis in this model, suggesting an important role for estrogens in the pathogenesis of HCC and suggesting that it should be tested in human beings as a chemopreventive agent against HCC.
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Affiliation(s)
- Adrian M Di Bisceglie
- Saint Louis University Liver Center, Department of Medicine, Saint Louis University, 3635 Vista Ave at Grand Blvd, MO 63110, USA.
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McMillian M, Nie AY, Parker JB, Leone A, Bryant S, Kemmerer M, Herlich J, Liu Y, Yieh L, Bittner A, Liu X, Wan J, Johnson MD. A gene expression signature for oxidant stress/reactive metabolites in rat liver. Biochem Pharmacol 2005; 68:2249-61. [PMID: 15498515 DOI: 10.1016/j.bcp.2004.08.003] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2004] [Accepted: 08/03/2004] [Indexed: 11/15/2022]
Abstract
Formation of free radicals and other reactive molecules is responsible for the adverse effects produced by a number of hepatotoxic compounds. cDNA microarray technology was used to compare transcriptional profiles elicited by training and testing sets of 15 oxidant stressors/reactive metabolite treatments to those produced by approximately 85 other paradigm compounds (mostly hepatotoxicants) to determine a shared signature profile for oxidant stress-associated hepatotoxicity. Initially, 100 genes were chosen that responded significantly different to oxidant stressors/reactive metabolites (OS/RM) compared to other samples in the database, then a 25-gene subset was selected by multivariate analysis. Many of the selected genes (e.g., aflatoxin aldehyde reductase, diaphorase, epoxide hydrolase, heme oxgenase and several glutathione transferases) are well-characterized oxidant stress/Nrf-2-responsive genes. Less than 10 other compounds co-cluster with our training and testing set compounds and these are known to generate OS/RMs as part of their mechanisms of toxicity. Using OS/RM signature gene sets, compounds previously associated with macrophage activation formed a distinct cluster separate from OS/RM and other compounds. A 69-gene set was chosen to maximally separate compounds in control, macrophage activator, peroxisome proliferator and OS/RM classes. The ease with which these 'oxidative stressor' classes can be separated indicates a role for microarray technology in early prediction and classification of hepatotoxicants. The ability to rapidly screen the oxidant stress potential of compounds may aid in avoidance of some idiosyncratic drug reactions as well as overtly toxic compounds.
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Affiliation(s)
- Michael McMillian
- Johnson and Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ, USA.
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Lu XG, Zhan LB, Feng BA, Qu MY, Yu LH, Xie JH. Inhibition of growth and metastasis of human gastric cancer implanted in nude mice by d-limonene. World J Gastroenterol 2004; 10:2140-4. [PMID: 15237454 PMCID: PMC4572353 DOI: 10.3748/wjg.v10.i14.2140] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the effects and mechanism of d-limonene on the growth and metastasis of gastric cancer in vivo.
METHODS: Metastatic model simulating human gastric cancer was established by orthotopic implantation of histologically intact human tumor tissue into gastric wall of nude mice. One percent d-limonene was orally administered at dose of 15 ml/kg every other day for seven weeks. Eight weeks after implantation, tumor weight, inhibition rate, apoptotic index (AI), microvessel density (MVD), vascular endothelial growth factor (VEGF), variation of ultrastructure, and the presence of metastasis were evaluated, respectively, after the mice were sacrificed.
RESULTS: The tumor weight was significantly reduced in 5-FU group (2.55 ± 0.28 g), d-limonene group (1.49 ± 0.09 g) and combined treatment group (1.48 ± 0.21 g) compared with the control group(2.73 ± 0.23 g, P < 0.05). In 5-FU group, d-limonene group, combined treatment group, the inhibition rates were 2.60%, 47.58% and 46.84% and 0, respectively; AI was (3.31 ± 0.33)%, (8.26 ± 1.21)%, (20.99 ± 1.84)% and (19.34 ± 2.19)%, respectively; MVD was (8.64 ± 2.81), (16.77 ± 1.39), (5.32 ± 4.26) and (5.86 ± 2.27), respectively; VEGF expression was (45.77 ± 4.79), (41.34 ± 5.41), (29.71 ± 8.92) and (28.24 ± 8.55), respectively. The incidences of peritoneal metastasis also decreased significantly in 5-FU group(77.8%), d-limonene group (20.0%) and combined group (22.2%) compared with control group (100%) versus 62.5%, 30% and 22.2%) (P < 0.05). Liver metastasis was also inhibited and the incidences decreased significantly in 5-FU group, d-limonene group and combined group than that in control group (87.5% vs 55.5%, 20.0% and 22.2% respectively) (P < 0.05). The incidence of ascites in control group, 5-FU group, d-limonene group and combined group was 25.0%, 22.2%, 0, 0, respectively and 12.5%, 11.1% 0, 0, with respect to the metastasis rate to other organs.
CONCLUSION: d-limonene has antiangiogenic and proapoptotic effects on gastric cancer, thereby inhibits tumor growth and metastasis. Combination of d-limonene with cytotoxic agents may be more effective.
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Affiliation(s)
- Xiao-Guang Lu
- Department of General Surgery, Fourth Hospital of Dalian Medical University, Dalian 116001, Liaoning Province, China.
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Weber LWD, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol 2004; 33:105-36. [PMID: 12708612 DOI: 10.1080/713611034] [Citation(s) in RCA: 1144] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The use of many halogenated alkanes such as carbon tetrachloride (CCl4), chloroform (CHCl3) or iodoform (CHI3), has been banned or severely restricted because of their distinct toxicity. Yet CCl4 continues to provide an important service today as a model substance to elucidate the mechanisms of action of hepatotoxic effects such as fatty degeneration, fibrosis, hepatocellular death, and carcinogenicity. In a matter of dose,exposure time, presence of potentiating agents, or age of the affected organism, regeneration can take place and lead to full recovery from liver damage. CCl4 is activated by cytochrome (CYP)2E1, CYP2B1 or CYP2B2, and possibly CYP3A, to form the trichloromethyl radical, CCl3*. This radical can bind to cellular molecules (nucleic acid, protein, lipid), impairing crucial cellular processes such as lipid metabolism, with the potential outcome of fatty degeneration (steatosis). Adduct formation between CCl3* and DNA is thought to function as initiator of hepatic cancer. This radical can also react with oxygen to form the trichloromethylperoxy radical CCl3OO*, a highly reactive species. CCl3OO* initiates the chain reaction of lipid peroxidation, which attacks and destroys polyunsaturated fatty acids, in particular those associated with phospholipids. This affects the permeabilities of mitochondrial, endoplasmic reticulum, and plasma membranes, resulting in the loss of cellular calcium sequestration and homeostasis, which can contribute heavily to subsequent cell damage. Among the degradation products of fatty acids are reactive aldehydes, especially 4-hydroxynonenal, which bind easily to functional groups of proteins and inhibit important enzyme activities. CCl4 intoxication also leads to hypomethylation of cellular components; in the case of RNA the outcome is thought to be inhibition of protein synthesis, in the case of phospholipids it plays a role in the inhibition of lipoprotein secretion. None of these processes per se is considered the ultimate cause of CCl4-induced cell death; it is by cooperation that they achieve a fatal outcome, provided the toxicant acts in a high single dose, or over longer periods of time at low doses. At the molecular level CCl4 activates tumor necrosis factor (TNF)alpha, nitric oxide (NO), and transforming growth factors (TGF)-alpha and -beta in the cell, processes that appear to direct the cell primarily toward (self-)destruction or fibrosis. TNFalpha pushes toward apoptosis, whereas the TGFs appear to direct toward fibrosis. Interleukin (IL)-6, although induced by TNFalpha, has a clearly antiapoptotic effect, and IL-10 also counteracts TNFalpha action. Thus, both interleukins have the potential to initiate recovery of the CCl4-damaged hepatocyte. Several of the above-mentioned toxication processes can be specifically interrupted with the use of antioxidants and mitogens, respectively, by restoring cellular methylation, or by preserving calcium sequestration. Chemicals that induce cytochromes that metabolize CCl4, or delay tissue regeneration when co-administered with CCl4 will potentiate its toxicity thoroughly, while appropriate CYP450 inhibitors will alleviate much of the toxicity. Oxygen partial pressure can also direct the course of CCl4 hepatotoxicity. Pressures between 5 and 35 mmHg favor lipid peroxidation, whereas absence of oxygen, as well as a partial pressure above 100 mmHg, both prevent lipid peroxidation entirely. Consequently, the location of CCl4-induced damage mirrors the oxygen gradient across the liver lobule. Mixed halogenated methanes and ethanes, found as so-called disinfection byproducts at low concentration in drinking water, elicit symptoms of toxicity very similar to carbon tetrachloride, including carcinogenicity.
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Affiliation(s)
- Lutz W D Weber
- Institute of Toxicology, GSF-National Research Center for Environment and Health, Munich, P.O. Box 1129, D-85758 Neuherberg (FRG).
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Wrona M, Rózanowska M, Sarna T. Zeaxanthin in combination with ascorbic acid or alpha-tocopherol protects ARPE-19 cells against photosensitized peroxidation of lipids. Free Radic Biol Med 2004; 36:1094-101. [PMID: 15082063 DOI: 10.1016/j.freeradbiomed.2004.02.005] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2003] [Revised: 01/08/2004] [Accepted: 02/02/2004] [Indexed: 11/28/2022]
Abstract
The antioxidant action of carotenoids is believed to involve quenching of singlet oxygen and scavenging of reactive oxygen radicals. However, the exact mechanism by which carotenoids protect cells against oxidative damage, particularly in the presence of other antioxidants, remains to be elucidated. This study was carried out to examine the ability of exogenous zeaxanthin alone and in combination with vitamin E or C, to protect cultured human retinal pigment epithelium cells against oxidative stress. The survival of ARPE-19 cells, subjected to merocyanine 540-mediated photodynamic action, was determined by the MTT test and the content of lipid hydroperoxides in photosensitized cells was analyzed by HPLC with electrochemical detection. We found that zeaxanthin-supplemented cells, in the presence of either alpha-tocopherol or ascorbic acid, were significantly more resistant to photoinduced oxidative stress. Cells with added antioxidants exhibited increased viability and accumulated less lipid hydroperoxides than cells without the antioxidant supplementation. Such a synergistic action of zeaxanthin and vitamin E or C indicates the importance of the antioxidant interaction in efficient protection of cell membranes against oxidative damage induced by photosensitized reactions.
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Affiliation(s)
- Marta Wrona
- Department of Biophysics, Faculty of Biotechnology, Jagiellonian University, Kraków, Poland
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Song HZ, Igarashi M, Kato M, Muto Y. In Vitro Study of the Chemopreventive Effects of Chinese Herbs against Hepatocarcinogenesis. J Clin Biochem Nutr 2004. [DOI: 10.3164/jcbn.35.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Birch NC, Radio S, Horslen S. Metastatic hepatocellular carcinoma in a patient with niemann-pick disease, type C. J Pediatr Gastroenterol Nutr 2003; 37:624-6. [PMID: 14581809 DOI: 10.1097/00005176-200311000-00023] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Nathan C Birch
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-6495, USA
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