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Stephen F Pernal - One of the best experts on this subject based on the ideXlab platform.
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determination of dicyclohexylamine in beeswax by aqueous normal phase liquid chromatography coupled with tandem mass spectrometry
Journal of Chromatographic Science, 2018Co-Authors: T S Thompson, Johan P Van Den Heever, Stephen F PernalAbstract:Dicyclohexylamine (DCH) is an excipient present in commercial formulations of Fumagillin (Fumagilin-B® and Fumidil-B®), an antibiotic which is employed in apiculture for the control of nosema disease. DCH has been demonstrated to be stable in harvested honey; however, its fate in the beehive has not been investigated. In this study, DCH residues were determined in beeswax samples collected from brood chambers and honey supers from various apiaries throughout Alberta. The determination of DCH was performed using a simple extraction procedure followed by low-temperature cleanup and finally analysis with aqueous normal phase liquid chromatography-electrospray ionization tandem mass spectrometry. The method was found to yield high accuracy and precision (94.9 ± 1.7% to 110.8 ± 6.6%) for replicate beeswax samples spiked with 4, 80, 360 and 2,000 μg kg-1 of DCH. With a limit of quantification of 1 μg kg-1, 100% of the 61 beeswax samples analyzed were found to contain residues of DCH ranging from 15 to 6,410 μg kg-1. The results indicate that DCH can accumulate in beeswax when Fumagilin-B® or Fumidil-B® is applied in apiculture and that these concentrations can vary significantly among beekeeping operations.
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The effect of dicyclohexylamine and Fumagillin on Nosema ceranae-infected honey bee (Apis mellifera) mortality in cage trial assays
Apidologie, 2016Co-Authors: Johan P Van Den Heever, Jonathan M Curtis, Abdullah Ibrahim, Thomas S. Thompson, Simon J. G. Otto, Stephen F PernalAbstract:AbstractBoth commercially available Fumagillin-based treatments for honey bees (Apis mellifera), Fumagilin-B® as well as Fumidil-B®, contain the reportedly genotoxic and tumorigenic compound dicyclohexylamine (DCH) as the counter ion in the Fumagillin-DCH salt. The effect of DCH, purified Fumagillin (containing no DCH), and the commercial formulation Fumagilin-B® (containing both Fumagillin as well as DCH) on the mortality of caged Nosema ceranae-infected honey bees was investigated. A statistically significant risk of bee mortality associated with oral exposure to DCH was observed. DCH is also known to be significantly more stable than Fumagillin in honey under a variety of temperature conditions, both in the presence and absence of light. The presence of DCH in the hive is therefore a potential concern for bee health and also for food safety.
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stability of dicyclohexylamine and Fumagillin in honey
Food Chemistry, 2015Co-Authors: Johan P Van Den Heever, T S Thompson, Jonathan M Curtis, Stephen F PernalAbstract:Abstract Fumagillin is extensively used to control nosema disease in apiculture. In the commercial formulation, Fumagillin is present as a salt in an equimolar quantity with dicyclohexylamine (DCH). In this study DCH was observed to be significantly more resistant to degradation in honey than Fumagillin using LC–MS/MS analysis. Observed half-lives for DCH ranged from a minimum of 368 days when kept at 34 °C in darkness, to a maximum of 852 days when stored at 21 °C in darkness. A maximum half-life of 246 days was observed for Fumagillin in samples kept in darkness at a temperature of 21 °C. The observed half-life of Fumagillin was estimated to be 3 days when exposed to light at 21 °C, and complete decomposition was observed after 30 days under the same conditions. The stability of DCH, combined with its genotoxicity and tumorigenic properties make it an important potential contaminant in honey destined for human consumption.
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determination of dicyclohexylamine and Fumagillin in honey by lc ms ms
Food Analytical Methods, 2015Co-Authors: Johan P Van Den Heever, T S Thompson, Jonathan M Curtis, Stephen F PernalAbstract:A reversed phase (RP) liquid chromatography tandem mass spectrometric (LC-MS/MS) method was developed and validated to confirm and quantitate trace levels of Fumagillin and dicyclohexylamine (DCH) residues in honey destined for human consumption. Chromatographic resolution of DCH and Fumagillin, including the latter’s biologically active UV degradation products, was achieved using a C18 analytical column. A deuterium labelled d10-DCH internal standard was synthesized in a one-pot reaction from readily available starting materials and was used to compensate for observed matrix affects when quantitating DCH in honey from different floral origins. Sample extraction was achieved by using reversed phase polymeric solid phase extraction (SPE) with recoveries (±RSD%) at 10, 100 and 500 ng g−1 for 18 replicates at each respective concentration calculated as 105.7 ± 10.8, 100.8 ± 9.3 and 104.3 ± 8.7 for Fumagillin and as 104.0 ± 5.9, 98.3 ± 6.9 and 104.0 ± 9.7 for DCH. Domestically produced honey samples (n = 16) were analyzed for Fumagillin and DCH, and screened for UV-decomposed Fumagillin, without having any prior knowledge of whether Fumagillin was used in the bee colonies from which the honeys were produced. No UV-decomposed Fumagillin could be detected in any of the samples. Fumagillin was detected in 11 of the 16 samples at levels below 10 ng g−1, and only in 2 samples at levels above 10 ng g−1 (11.9 and 11.6 ng g−1, respectively). DCH was detected in all of the tested samples with concentrations above 10 ng g−1 being observed for 15 out of the 16 samples, with concentrations ranging from 20.0 to 234.6 ng g−1.
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Fumagillin an overview of recent scientific advances and their significance for apiculture
Journal of Agricultural and Food Chemistry, 2014Co-Authors: Johan P Van Den Heever, T S Thompson, Jonathan M Curtis, Abdullah Ibrahim, Stephen F PernalAbstract:Fumagillin is a potent fungal metabolite first isolated from Aspergillus fumigatus. It is widely used in apiculture and human medicine against a variety of microsporidian fungal infections. It has been the subject of research in cancer treatments by employing its angiogenesis inhibitory properties. The toxicity of Fumagillin has limited its use for human applications and spurred the development of analogues using structure-activity relationships relating to its angiogenesis properties. These discoveries may hold the key to the development of alternative chemical treatments for use in apiculture. The toxicity of Fumagillin to humans is important for beekeeping, because any residues remaining in hive products pose a direct risk to the consumer. The analytical methods published to date measure Fumagillin and its decomposition products but overlook the dicyclohexylamine counterion of the salt form widely used in apiculture.
Johan P Van Den Heever - One of the best experts on this subject based on the ideXlab platform.
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determination of dicyclohexylamine in beeswax by aqueous normal phase liquid chromatography coupled with tandem mass spectrometry
Journal of Chromatographic Science, 2018Co-Authors: T S Thompson, Johan P Van Den Heever, Stephen F PernalAbstract:Dicyclohexylamine (DCH) is an excipient present in commercial formulations of Fumagillin (Fumagilin-B® and Fumidil-B®), an antibiotic which is employed in apiculture for the control of nosema disease. DCH has been demonstrated to be stable in harvested honey; however, its fate in the beehive has not been investigated. In this study, DCH residues were determined in beeswax samples collected from brood chambers and honey supers from various apiaries throughout Alberta. The determination of DCH was performed using a simple extraction procedure followed by low-temperature cleanup and finally analysis with aqueous normal phase liquid chromatography-electrospray ionization tandem mass spectrometry. The method was found to yield high accuracy and precision (94.9 ± 1.7% to 110.8 ± 6.6%) for replicate beeswax samples spiked with 4, 80, 360 and 2,000 μg kg-1 of DCH. With a limit of quantification of 1 μg kg-1, 100% of the 61 beeswax samples analyzed were found to contain residues of DCH ranging from 15 to 6,410 μg kg-1. The results indicate that DCH can accumulate in beeswax when Fumagilin-B® or Fumidil-B® is applied in apiculture and that these concentrations can vary significantly among beekeeping operations.
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The effect of dicyclohexylamine and Fumagillin on Nosema ceranae-infected honey bee (Apis mellifera) mortality in cage trial assays
Apidologie, 2016Co-Authors: Johan P Van Den Heever, Jonathan M Curtis, Abdullah Ibrahim, Thomas S. Thompson, Simon J. G. Otto, Stephen F PernalAbstract:AbstractBoth commercially available Fumagillin-based treatments for honey bees (Apis mellifera), Fumagilin-B® as well as Fumidil-B®, contain the reportedly genotoxic and tumorigenic compound dicyclohexylamine (DCH) as the counter ion in the Fumagillin-DCH salt. The effect of DCH, purified Fumagillin (containing no DCH), and the commercial formulation Fumagilin-B® (containing both Fumagillin as well as DCH) on the mortality of caged Nosema ceranae-infected honey bees was investigated. A statistically significant risk of bee mortality associated with oral exposure to DCH was observed. DCH is also known to be significantly more stable than Fumagillin in honey under a variety of temperature conditions, both in the presence and absence of light. The presence of DCH in the hive is therefore a potential concern for bee health and also for food safety.
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stability of dicyclohexylamine and Fumagillin in honey
Food Chemistry, 2015Co-Authors: Johan P Van Den Heever, T S Thompson, Jonathan M Curtis, Stephen F PernalAbstract:Abstract Fumagillin is extensively used to control nosema disease in apiculture. In the commercial formulation, Fumagillin is present as a salt in an equimolar quantity with dicyclohexylamine (DCH). In this study DCH was observed to be significantly more resistant to degradation in honey than Fumagillin using LC–MS/MS analysis. Observed half-lives for DCH ranged from a minimum of 368 days when kept at 34 °C in darkness, to a maximum of 852 days when stored at 21 °C in darkness. A maximum half-life of 246 days was observed for Fumagillin in samples kept in darkness at a temperature of 21 °C. The observed half-life of Fumagillin was estimated to be 3 days when exposed to light at 21 °C, and complete decomposition was observed after 30 days under the same conditions. The stability of DCH, combined with its genotoxicity and tumorigenic properties make it an important potential contaminant in honey destined for human consumption.
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determination of dicyclohexylamine and Fumagillin in honey by lc ms ms
Food Analytical Methods, 2015Co-Authors: Johan P Van Den Heever, T S Thompson, Jonathan M Curtis, Stephen F PernalAbstract:A reversed phase (RP) liquid chromatography tandem mass spectrometric (LC-MS/MS) method was developed and validated to confirm and quantitate trace levels of Fumagillin and dicyclohexylamine (DCH) residues in honey destined for human consumption. Chromatographic resolution of DCH and Fumagillin, including the latter’s biologically active UV degradation products, was achieved using a C18 analytical column. A deuterium labelled d10-DCH internal standard was synthesized in a one-pot reaction from readily available starting materials and was used to compensate for observed matrix affects when quantitating DCH in honey from different floral origins. Sample extraction was achieved by using reversed phase polymeric solid phase extraction (SPE) with recoveries (±RSD%) at 10, 100 and 500 ng g−1 for 18 replicates at each respective concentration calculated as 105.7 ± 10.8, 100.8 ± 9.3 and 104.3 ± 8.7 for Fumagillin and as 104.0 ± 5.9, 98.3 ± 6.9 and 104.0 ± 9.7 for DCH. Domestically produced honey samples (n = 16) were analyzed for Fumagillin and DCH, and screened for UV-decomposed Fumagillin, without having any prior knowledge of whether Fumagillin was used in the bee colonies from which the honeys were produced. No UV-decomposed Fumagillin could be detected in any of the samples. Fumagillin was detected in 11 of the 16 samples at levels below 10 ng g−1, and only in 2 samples at levels above 10 ng g−1 (11.9 and 11.6 ng g−1, respectively). DCH was detected in all of the tested samples with concentrations above 10 ng g−1 being observed for 15 out of the 16 samples, with concentrations ranging from 20.0 to 234.6 ng g−1.
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Fumagillin an overview of recent scientific advances and their significance for apiculture
Journal of Agricultural and Food Chemistry, 2014Co-Authors: Johan P Van Den Heever, T S Thompson, Jonathan M Curtis, Abdullah Ibrahim, Stephen F PernalAbstract:Fumagillin is a potent fungal metabolite first isolated from Aspergillus fumigatus. It is widely used in apiculture and human medicine against a variety of microsporidian fungal infections. It has been the subject of research in cancer treatments by employing its angiogenesis inhibitory properties. The toxicity of Fumagillin has limited its use for human applications and spurred the development of analogues using structure-activity relationships relating to its angiogenesis properties. These discoveries may hold the key to the development of alternative chemical treatments for use in apiculture. The toxicity of Fumagillin to humans is important for beekeeping, because any residues remaining in hive products pose a direct risk to the consumer. The analytical methods published to date measure Fumagillin and its decomposition products but overlook the dicyclohexylamine counterion of the salt form widely used in apiculture.
Jonathan M Curtis - One of the best experts on this subject based on the ideXlab platform.
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The effect of dicyclohexylamine and Fumagillin on Nosema ceranae-infected honey bee (Apis mellifera) mortality in cage trial assays
Apidologie, 2016Co-Authors: Johan P Van Den Heever, Jonathan M Curtis, Abdullah Ibrahim, Thomas S. Thompson, Simon J. G. Otto, Stephen F PernalAbstract:AbstractBoth commercially available Fumagillin-based treatments for honey bees (Apis mellifera), Fumagilin-B® as well as Fumidil-B®, contain the reportedly genotoxic and tumorigenic compound dicyclohexylamine (DCH) as the counter ion in the Fumagillin-DCH salt. The effect of DCH, purified Fumagillin (containing no DCH), and the commercial formulation Fumagilin-B® (containing both Fumagillin as well as DCH) on the mortality of caged Nosema ceranae-infected honey bees was investigated. A statistically significant risk of bee mortality associated with oral exposure to DCH was observed. DCH is also known to be significantly more stable than Fumagillin in honey under a variety of temperature conditions, both in the presence and absence of light. The presence of DCH in the hive is therefore a potential concern for bee health and also for food safety.
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stability of dicyclohexylamine and Fumagillin in honey
Food Chemistry, 2015Co-Authors: Johan P Van Den Heever, T S Thompson, Jonathan M Curtis, Stephen F PernalAbstract:Abstract Fumagillin is extensively used to control nosema disease in apiculture. In the commercial formulation, Fumagillin is present as a salt in an equimolar quantity with dicyclohexylamine (DCH). In this study DCH was observed to be significantly more resistant to degradation in honey than Fumagillin using LC–MS/MS analysis. Observed half-lives for DCH ranged from a minimum of 368 days when kept at 34 °C in darkness, to a maximum of 852 days when stored at 21 °C in darkness. A maximum half-life of 246 days was observed for Fumagillin in samples kept in darkness at a temperature of 21 °C. The observed half-life of Fumagillin was estimated to be 3 days when exposed to light at 21 °C, and complete decomposition was observed after 30 days under the same conditions. The stability of DCH, combined with its genotoxicity and tumorigenic properties make it an important potential contaminant in honey destined for human consumption.
-
determination of dicyclohexylamine and Fumagillin in honey by lc ms ms
Food Analytical Methods, 2015Co-Authors: Johan P Van Den Heever, T S Thompson, Jonathan M Curtis, Stephen F PernalAbstract:A reversed phase (RP) liquid chromatography tandem mass spectrometric (LC-MS/MS) method was developed and validated to confirm and quantitate trace levels of Fumagillin and dicyclohexylamine (DCH) residues in honey destined for human consumption. Chromatographic resolution of DCH and Fumagillin, including the latter’s biologically active UV degradation products, was achieved using a C18 analytical column. A deuterium labelled d10-DCH internal standard was synthesized in a one-pot reaction from readily available starting materials and was used to compensate for observed matrix affects when quantitating DCH in honey from different floral origins. Sample extraction was achieved by using reversed phase polymeric solid phase extraction (SPE) with recoveries (±RSD%) at 10, 100 and 500 ng g−1 for 18 replicates at each respective concentration calculated as 105.7 ± 10.8, 100.8 ± 9.3 and 104.3 ± 8.7 for Fumagillin and as 104.0 ± 5.9, 98.3 ± 6.9 and 104.0 ± 9.7 for DCH. Domestically produced honey samples (n = 16) were analyzed for Fumagillin and DCH, and screened for UV-decomposed Fumagillin, without having any prior knowledge of whether Fumagillin was used in the bee colonies from which the honeys were produced. No UV-decomposed Fumagillin could be detected in any of the samples. Fumagillin was detected in 11 of the 16 samples at levels below 10 ng g−1, and only in 2 samples at levels above 10 ng g−1 (11.9 and 11.6 ng g−1, respectively). DCH was detected in all of the tested samples with concentrations above 10 ng g−1 being observed for 15 out of the 16 samples, with concentrations ranging from 20.0 to 234.6 ng g−1.
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Fumagillin an overview of recent scientific advances and their significance for apiculture
Journal of Agricultural and Food Chemistry, 2014Co-Authors: Johan P Van Den Heever, T S Thompson, Jonathan M Curtis, Abdullah Ibrahim, Stephen F PernalAbstract:Fumagillin is a potent fungal metabolite first isolated from Aspergillus fumigatus. It is widely used in apiculture and human medicine against a variety of microsporidian fungal infections. It has been the subject of research in cancer treatments by employing its angiogenesis inhibitory properties. The toxicity of Fumagillin has limited its use for human applications and spurred the development of analogues using structure-activity relationships relating to its angiogenesis properties. These discoveries may hold the key to the development of alternative chemical treatments for use in apiculture. The toxicity of Fumagillin to humans is important for beekeeping, because any residues remaining in hive products pose a direct risk to the consumer. The analytical methods published to date measure Fumagillin and its decomposition products but overlook the dicyclohexylamine counterion of the salt form widely used in apiculture.
Zoran Stanimirovic - One of the best experts on this subject based on the ideXlab platform.
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potential of Fumagillin and agaricus blazei mushroom extract to reduce nosema ceranae in honey bees
Insects, 2021Co-Authors: Uros Glavinic, Jevrosima Stevanovic, Marko Ristanic, Milan Rajkovic, Dajana Davitkov, Nada Lakic, Zoran StanimirovicAbstract:Depending on the infection level and colony strength, Nosema ceranae, a microsporidian endoparasite of the honey bee may have significant consequences on the health, reproduction and productivity of bee colonies. Despite exerting some side effects, Fumagillin is most often used for Nosema control. In this study, in a cage experiment, N. ceranae infected bees were treated with Fumagillin or the extract of Agaricus blazei mushroom, a possible alternative for Nosema control. Bee survival, Nosema spore loads, the expression levels of immune-related genes and parameters of oxidative stress were observed. Fumagillin treatment showed a negative effect on monitored parameters when applied preventively to non-infected bees, while a noticeable anti-Nosema effect and protection from Nosema-induced immunosuppression and oxidative stress were proven in Nosema-infected bees. However, a protective effect of the natural A. blazei extract was detected, without any side effects but with immunostimulatory activity in the preventive application. The results of this research suggest the potential of A. blazei extract for Nosema control, which needs to be further investigated.
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In vitro evaluation of the clastogenicity of Fumagillin.
Environmental and molecular mutagenesis, 2008Co-Authors: Jevrosima Stevanovic, Zoran Stanimirovic, Milena Radakovic, Velibor StojićAbstract:Fumagillin, an antibiotic compound produced by Aspergillus fumigatus, is effective against microsporidia and various Amoeba species, but is also toxic when administered systemically to mammals. Furthermore, a recent in vivo study by Stanimirovic Z et al. 2007: (Mutat Res 628:1–10) indicated genotoxic effects of Fumagillin. The aim of the present study was to investigate and explain the clastogenic effects of Fumagillin (in the form of Fumagillin dicyclohexylamine salt) on human peripheral blood lymphocytes in vitro by sister-chromatid exchanges (SCE), chromosome aberrations (CA), and micronucleus (MN) tests. The mitotic index (MI), proliferation index (PI), and nuclear division index (NDI) were calculated to evaluate the cytotoxic potential of Fumagillin. Five concentrations of Fumagillin (0.34, 0.68, 1.02, 3.07, and 9.20 μg/ml) were applied to lymphocyte cultures. All the tested concentrations of Fumagillin increased the frequency of SCE per cell significantly (P < 0.001 or P < 0.01) compared with the negative control. A significant (P < 0.001) increase in frequency of structural CA was observed at the three highest concentrations in comparison with the negative control. In addition, the three highest test concentrations increased MN formation and decreased MI, PI, and NDI significantly compared with the negative control. The present results indicate that Fumagillin is clastogenic and cytotoxic to cultured human lymphocytes. Environ. Mol. Mutagen., 2008. © 2008 Wiley-Liss, Inc.
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evaluation of genotoxic effects of Fumagillin by cytogenetic tests in vivo
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2007Co-Authors: Zoran Stanimirovic, Jevrosima Stevanovic, Vladan Bajic, Ivica RadovicAbstract:Fumagillin is a naturally secreted antibiotic of the fungus Aspergillus fumigatus. It is used in veterinary medicine against microsporidiosis of bees and fish. In this study, the genotoxicity of Fumagillin (in the form of Fumagillin dicyclohexylamine) was evaluated in mouse bone-marrow cells using the mitotic index (MI), the chromosome aberration (CA) assay, and the micronucleus (MN) test. Fumagillin was administered to BALB/c mice by gavage, at doses of 25, 50, 75 mg/kg body weight (bw), repeated for 7 days at 24-h intervals, with water-sugar syrup as a negative control and cyclophosphamide (40 mg/kg bw) as a positive control. All experimental doses of Fumagillin induced a significant decrease (p<0.001) in MI (3.47+/-0.04%, 3.17+/-0.01%, and 2.27+/-0.02%, respectively) in comparison with the negative control (6.00+/-0.01%). Fumagillin significantly (p<0.001) increased the frequency of MN (4.98+/-0.35, 8.45+/-0.57, and 12.02+/-0.37, respectively) over negative control (1.04+/-0.28). Significantly increased frequencies (p<0.01 or p<0.001) of numerical chromosomal aberrations (aneuploidies and polyploidies) and structural chromosomal aberrations such as gaps, breaks, and centric rings were observed at the highest experimental dose of Fumagillin (75 mg/kg bw) compared with the negative control. However, with respect to the induction of Robertsonian translocations, both the intermediate (50 mg/kg bw) and highest (75 mg/kg bw) experimental dose caused a significant (p<0.001) increase (7.12+/-0.26 and 9.00+/-0.10, respectively) in comparison with the negative control (0.00+/-0.00). Chromosomes 4 and 19 participated in these Robertsonian translocations. Regarding total cytogenetic changes, a significant increase (p<0.001) was observed in both the intermediate dose group (17.36+/-1.83) and the highest dose group (59.49+/-1.92) compared with the negative control (7.00+/-1.35). These results suggest that Fumagillin has genotoxic (clastogenic) potential in mammals in vivo.
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frequency of chromosomal aberrations in the evaluation of genotoxic potential of dicyclohexylamine Fumagillin in vivo
Acta Veterinaria-beograd, 2006Co-Authors: Zoran Stanimirovic, Stevanovic Jevrosima, Milan Kulic, Velibor StojicAbstract:Dicyclohexylamine (Fumagillin), as an antibiotic produced by fermentation of Aspergillus fumigatus, is used in human medicine for the treatment of intestinal microsporidiosis in patients with HIV infection, intestinal amebiasis and microsporidial keratoconjunctivitis. In veterinary medicine Fumagillin is effective in suppressing microsporidiosis of bees and fish. In this study, the genotoxicity of Fumagillin was evaluated in mouse bone marrow cells using chromosome aberrations (CA) assay. Dicyclohexylamine was administered to mice by gavage in a dose of 25, 50, 75 mg/kg b.w., with water-sugar syrup as the negative control and cyclophosphamide as the positive control (40 mg/kg b.w) Significantly increased frequency (p<0.01 or p<0.001) of numerical chromosomal aberrations (aneupliodies and polyploidies) and structural chromosomal aberrations of gaps, breaks and centric rings were observed only at the highest experimental dose of dicyclohexylamine, compared with the negative control. However, in point of induction of Rb translocations, both the median (50 mg/kg b.w) and highest (75 mg/kg b.w) experimental dose showed a significant (p<00.001) increase (7.12 ± 0.26 and 9.00 ± 0.10, respectively) in comparison with the negative control (0.00 ± 0.00). Chromosomes 4 and 19 participated in these Rb translocations. These results suggest that dicyclohexilamine (Fumagillin) has genotoxic potential in mammal in vivo chromosomal aberration (CA) test system.
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monitoring of mitotic index and frequency of micronuclei in evaluation of genotoxic potential of Fumagillin dicyclohexylamine in vivo
Acta Veterinaria-beograd, 2006Co-Authors: Jevrosima Stevanovic, Zoran Stanimirovic, Ivana I Pejin, Miodrag LazarevicAbstract:Fumagillin (dicyclohexylamine) is a natural antibiotic, secreted by Aspergillus fumigatus. It is used in veterinary medicine against microsporidiosis in bees and fish, as well as in human medicine for the treatment of intestinal amebiasis, microsporidial keratoconjunctivitis and intestinal microsporidiosis due to Enterocytozoon bieneusi in patients with AIDS and other types of immunodeficiency. In this study, the genotoxicity of Fumagillin was evaluated in mouse bone marrow cells using the mitotic index (MI) and micronucleus (MN) assay. Fumagillin was administered to BALB/c mice by gavage in doses of 25, 50, 75 mg/kg b.w., repeated for 7 days at 24h intervals, with water-sugar syrup as the negative control and cyclophosphamide as the positive control (40 mg/kg b.w) All experimental doses of Fumagillin induced a significant decrease (p<0.001) in MI (3.47 ± 0.04%, 3.17 ± 0.01% and 2.27 ± 0.02%, respectively) in comparison with the negative control (6.00 ± 0.01%) and with the positive control (14.78 ± 0.09). Fumagillin significantly (p<0.001) increased the frequency of MN (4.98 ± 0.35, 8.45 ± 0.57 and 12.02 ± 0.37, respectively) over the negative control (1.04 ± 0.28). These results suggest that Fumagillin (dicyclohexilamine) has an antiproliferative and genotoxic potential in mammal in vivo test.
Reza Forough - One of the best experts on this subject based on the ideXlab platform.
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fgfr1 pi3k akt signaling pathway is a novel target for antiangiogenic effects of the cancer drug Fumagillin tnp 470
Journal of Cellular Biochemistry, 2007Co-Authors: Gregory J Chen, Brian Weylie, James Zhu, Reza ForoughAbstract:Fibroblast growth factor-1 (FGF1), a prototypic member of the FGF family, is a potent angiogenic factor. Although FGF-stimulated angiogenesis has been extensively studied, the molecular mechanisms regulating FGF1-induced angiogenesis are poorly understood in vivo. Fumagillin, an antiangiogenic fungal metabolite, has the ability to inhibit FGF-stimulated angiogenesis in the chicken chorioallantoic membrane (CAM). In the current study, chicken CAMs were transfected with a signal peptide-containing version of the FGF1 gene construct (sp-FGF1). Transfected CAMs were then analyzed in the presence and absence of Fumagillin treatment with respect to the mRNA expression levels and protein activity of the FGF1 receptor protein (FGFR1), phosphatidylinositol 3-kinase (PI3K), and its immediate downstream target, AKT-1 (protein kinase B). Treatment of sp-FGF1-transfected CAMs with Fumagillin showed downregulation for both PI3K and AKT-1 proteins in mRNA expression and protein activity. In contrast, no major alterations in FGFR1 mRNA expression level were observed. Similar patterns of mRNA expression for the above three proteins were observed when the CAMs were treated with recombinant FGF1 protein in place of sp-FGF1 gene transfection. Investigation using biotin-labeled Fumagillin showed that only the FGF1 receptor protein containing the cytoplasmic domain demonstrated binding to Fumagillin. Furthermore, we demonstrated endothelial-specificity of the proposed antiangiogenic signaling cascade using an in vitro system. Based on these findings, we conclude that the binding of Fumagillin to the cytoplasmic domain of the FGF1 receptor inhibited FGF1-stimulated angiogenesis both in vitro and in vivo.
