The Experts below are selected from a list of 279 Experts worldwide ranked by ideXlab platform
Sharon A. Meyer - One of the best experts on this subject based on the ideXlab platform.
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indole diterpene alkaloids as novel inhibitors of the wnt β catenin pathway in breast cancer cells
European Journal of Medicinal Chemistry, 2013Co-Authors: Asmaa A Sallam, Nehad M. Ayoub, Sharon A. Meyer, Chris R. Gissendanner, Ahmed I Foudah, Khalid El A SayedAbstract:Abstract Penitrems are indole diterpene alkaloids best known for their BK channel inhibition and tremorgenic effects in mammals. In a previous study, penitrems A–F ( 1 – 5 ), their biosynthetic precursors, paspaline ( 6 ) and emindole SB ( 7 ), and two brominated penitrem analogs 8 and 9 demonstrated promising in vitro antiproliferative, antimigratory, and anti-invasive effects in the MTT (MCF-7 and MDA-MB-231), wound-healing, and Cultrex ® BME cell invasion (MDA-MB-231) assays, respectively. The study herein reports the novel ability of penitrem A to suppress total β-catenin levels in MDA-MB-231 mammary cancer cells. Nine new penitrem analogs ( 10 – 18 ) were semisynthetically prepared, in an attempt to identify pharmacophores correlated with BK channel inhibition and tremorgenicity of penitrems and decrease their toxicity. The degree of BK channel inhibition was assessed using the nematode Caenorhabditis elegans , and in vivo tremorgenic EC 50 was calculated using CD-1 male mice following an Up-and-down Procedure (UDP). Although new analogs were generally less active than parent compound 1 , some showed no BK channel inhibition or tremorgenicity and retained the ability of penitrem A ( 1 ) to suppress total β-catenin levels in MDA-MB-231 cells. Paspaline ( 6 ) and emindole SB ( 7 ), both lacking BK channel inhibition and tremorgenicity, represent the simplest indole diterpene skeleton that retains the antiproliferative, antimigratory and total β-catenin suppressing effects shown by the more complex penitrem A ( 1 ).
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Indole diterpene alkaloids as novel inhibitors of the Wnt/β-catenin pathway in breast cancer cells.
European journal of medicinal chemistry, 2013Co-Authors: Asmaa A Sallam, Nehad M. Ayoub, Sharon A. Meyer, Chris R. Gissendanner, Ahmed I Foudah, Khalid A. El SayedAbstract:Abstract Penitrems are indole diterpene alkaloids best known for their BK channel inhibition and tremorgenic effects in mammals. In a previous study, penitrems A–F ( 1 – 5 ), their biosynthetic precursors, paspaline ( 6 ) and emindole SB ( 7 ), and two brominated penitrem analogs 8 and 9 demonstrated promising in vitro antiproliferative, antimigratory, and anti-invasive effects in the MTT (MCF-7 and MDA-MB-231), wound-healing, and Cultrex ® BME cell invasion (MDA-MB-231) assays, respectively. The study herein reports the novel ability of penitrem A to suppress total β-catenin levels in MDA-MB-231 mammary cancer cells. Nine new penitrem analogs ( 10 – 18 ) were semisynthetically prepared, in an attempt to identify pharmacophores correlated with BK channel inhibition and tremorgenicity of penitrems and decrease their toxicity. The degree of BK channel inhibition was assessed using the nematode Caenorhabditis elegans , and in vivo tremorgenic EC 50 was calculated using CD-1 male mice following an Up-and-down Procedure (UDP). Although new analogs were generally less active than parent compound 1 , some showed no BK channel inhibition or tremorgenicity and retained the ability of penitrem A ( 1 ) to suppress total β-catenin levels in MDA-MB-231 cells. Paspaline ( 6 ) and emindole SB ( 7 ), both lacking BK channel inhibition and tremorgenicity, represent the simplest indole diterpene skeleton that retains the antiproliferative, antimigratory and total β-catenin suppressing effects shown by the more complex penitrem A ( 1 ).
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Up-and-down Procedure (UDP) determinations of acute oral toxicity of nitroso degradation products of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX).
Journal of applied toxicology : JAT, 2005Co-Authors: Sharon A. Meyer, Adam J. Marchand, Jennifer L. Hight, George H. Roberts, Lynn Escalon, Laura S. Inouye, Denise K. MacmillanAbstract:Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a widely used military explosive and soil and ground water contaminant of munitions manufacturing and artillery training sites, undergoes microbial nitroreductase metabolism to hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine (DNX), and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX). Human occupational and accidental exposures to RDX, as well as acute oral exposures in rats, result in seizures, but little is known about the toxicity of the RDX degradation products. The main objective of the present study was to determine the oral LD50 of the most potent RDX N-nitroso product in female Sprague-Dawley rats using the recently validated Up-and-down Procedure (UDP). With only 26 rats, MNX was identified as the most potent metabolite and a maximum likelihood estimate of 187 mg kg−1 (95% confidence interval 118–491 mg kg−1) for its LD50 was established and found equivalent to that of RDX determined with the same protocol. CNS toxicity, manifested as forelimb clonic seizures progressing to generalized clonic-tonic seizures, was the critical adverse effect. Further, confirmation of the UDP LD50 for MNX with a fixed-dose design enabled identification of 94 mg kg−1 as the highest nonlethal dose. An ED50 of 57 mg kg−1 was determined for neurotoxicity, while splenic hemosiderosis and decreased blood hematocrit and hemoglobin concentration occurred with a threshold at 94 mg kg−1 in 14-day survivors. These studies, while providing new toxicity data necessary for the management of RDX-contaminated sites, illustrate the efficiency of the UDP for comparative acute toxicity determinations and its value in guiding further characterization of dose dependency of identified adverse effects. Copyright © 2005 John Wiley & Sons, Ltd.
Denise K. Macmillan - One of the best experts on this subject based on the ideXlab platform.
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Up-and-down Procedure (UDP) determinations of acute oral toxicity of nitroso degradation products of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX).
Journal of applied toxicology : JAT, 2005Co-Authors: Sharon A. Meyer, Adam J. Marchand, Jennifer L. Hight, George H. Roberts, Lynn Escalon, Laura S. Inouye, Denise K. MacmillanAbstract:Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a widely used military explosive and soil and ground water contaminant of munitions manufacturing and artillery training sites, undergoes microbial nitroreductase metabolism to hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine (DNX), and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX). Human occupational and accidental exposures to RDX, as well as acute oral exposures in rats, result in seizures, but little is known about the toxicity of the RDX degradation products. The main objective of the present study was to determine the oral LD50 of the most potent RDX N-nitroso product in female Sprague-Dawley rats using the recently validated Up-and-down Procedure (UDP). With only 26 rats, MNX was identified as the most potent metabolite and a maximum likelihood estimate of 187 mg kg−1 (95% confidence interval 118–491 mg kg−1) for its LD50 was established and found equivalent to that of RDX determined with the same protocol. CNS toxicity, manifested as forelimb clonic seizures progressing to generalized clonic-tonic seizures, was the critical adverse effect. Further, confirmation of the UDP LD50 for MNX with a fixed-dose design enabled identification of 94 mg kg−1 as the highest nonlethal dose. An ED50 of 57 mg kg−1 was determined for neurotoxicity, while splenic hemosiderosis and decreased blood hematocrit and hemoglobin concentration occurred with a threshold at 94 mg kg−1 in 14-day survivors. These studies, while providing new toxicity data necessary for the management of RDX-contaminated sites, illustrate the efficiency of the UDP for comparative acute toxicity determinations and its value in guiding further characterization of dose dependency of identified adverse effects. Copyright © 2005 John Wiley & Sons, Ltd.
George P. Cobb - One of the best experts on this subject based on the ideXlab platform.
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Age dependent acute oral toxicity of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and two anaerobic N-nitroso metabolites in deer mice (Peromyscus maniculatus).
Chemosphere, 2007Co-Authors: Jordan N. Smith, Marina A. Espino, George P. CobbAbstract:Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) transforms anaerobically into N-nitroso compounds: hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine (DNX), and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX). Exposure to these N-nitroso metabolites may occur in areas contaminated with explosives, as anaerobic degradation occurs via some bacteria and is one remediation strategy used for RDX. Few papers report acute oral toxicity and none have evaluated age dependent toxicity of RDX or its N-nitroso metabolites. Median lethal dose (LD50) was determined in deer mice (Peromyscus maniculatus) of three age classifications 21 d, 50 d, and 200 d for RDX, MNX, and TNX using the US EPA Up-and-down Procedure (UDP). Hexahydro-1,3,5-trinitro-1,3,5-triazine and N-nitroso metabolites caused similar overt signs of toxicity. Median lethal dose for 21 d deer mice were 136, 181, and 338 mg/kg for RDX, MNX, and TNX, respectively. Median lethal dose for 50 d deer mice were 319, 575, and 338 mg/kg for RDX, MNX, and TNX, respectively. Median lethal dose for 200 d deer mice were 158, 542, and 999 mg/kg for RDX, MNX, and TNX, respectively. These data suggest that RDX is the most potent compound tested, and age dependent toxicity may exist for all compounds and could play a role in RDX and RDX N-nitroso metabolite ecological risk evaluation of terrestrial wildlife at RDX contaminated sites.
A.a. Adeneye - One of the best experts on this subject based on the ideXlab platform.
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In vivo Safety Evaluation of a Nigerian Polyherbal Mixture in Female Wistar Rats.
Nigerian journal of physiological sciences : official publication of the Physiological Society of Nigeria, 2019Co-Authors: O M Olutimehin, A.a. Adeneye, O Awodele, S S SoyemiAbstract:The present study evaluates the oral safety and oral toxicity reversibility of a Nigerian Polyherbal Mixture (NPM) in female Wistar rats. In this study, acute oral toxicity was conducted on 20 female Wistar rats using the limit dose test of Up-and-down Procedure of the OECD Acute Oral Toxicity Testing 425 guidelines at 5000 mg/kg of NPM. Additionally, 40 female Wistar rats (120-150 g) were divided into 4 groups (n=10) and orally treated with 10ml/kg of distilled water, 82 mg/kg, 410 mg/kg and 2050 mg/kg of NPM, respectively, for 90 days. Five rats from each group were sacrificed while the remaining rats in each group were kept for another 14 days for oral toxicities reversibility test. Blood samples and vital organs were obtained for biochemical, hematological and histological changes. Results showed that acute oral toxicity testing of NPM caused no death in any of the three sequentially treated rats and its estimated LD50 value was greater than 5000 mg/kg. Chronic oral treatment with 82-2050 mg/kg NPM caused significant elevations in the serum urea and creatinine and full blood count parameters (except differential WBC counts). The elevated renal function parameters were corroborated by dose-related histological changes of renal tubular congestions. also caused profound thrombocytosis and histopathological changes of pulmonary interstitial widening and gastritis. In conclusion, NPM may not be considered safe for consumption on prolonged use and at a high dose due to its profound tendencies to cause pulmonary fibrosis, nephrotoxicity, gastritis and thrombo-embolism. However, all the biochemical and hematological but histopathological alterations induced by NPM were reversed 14 days after the treatment cessation.
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Pharmacological evaluation of oral hypoglycemic and antidiabetic effects of fresh leaves ethanol extract of morinda lucida benth. in normal and alloxan- induced diabetic rats
African Journal of Biomedical Research, 2010Co-Authors: A.a. Adeneye, Esther Oluwatoyin AgbajeAbstract:In the present study, 50 – 400 mg/kg of body weight/day of 50% ethanol extract of the fresh leaves of Morinda lucida Benth. (MLE) was investigated for its hypoglycemic and antidiabetic effects in adult normal and alloxaninduced diabetic male rats for 7 days. Acute oral toxicity study of MLE at the limit dose of 2000 mg/kg of body weight using Up-and-down Procedure on statistical program, AOT425Pgm, was also conducted. Results showed that MLE significantly (p
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Pharmacological Evaluation of a Nigerian Polyherbal Health Tonic Tea in Rat
African Journal of Biomedical Research, 2010Co-Authors: A.a. Adeneye, A.s BeneboAbstract:The present study is a fourteen day study, designed to investigate the hematological and biochemical effects of single, daily oral doses of 100 – 600 mg/kg of a Nigerian Polyherbal Tonic Tea (PHT) in four groups of adult Wistar rats. Acute oral toxicity test of PHT at the limit dose of 5000 mg/kg was also conducted using Up-and-down Procedure on statistical software program (AOT425StatPgm, Version 1.0.). Results showed PHT to induce significant (p
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Hypoglycemic effects of the aqueous seed extract of Hunteria umbellata in normoglycemic and glucose and nicotine induced hyperglycemic rats
Planta Medica, 2008Co-Authors: A.a. Adeneye, Olufunmilayo O. AdeyemiAbstract:Summary: Dry seeds of the plant, Hunteria umbellata K. Schum (family: Apocynaceae), are highly valued in African traditional medicine in the treatment of various human diseases, including diabetes mellitus and obesity. In the present study, the hypoglycaemic and weight loss effects of 50 - 200 mg/kg of the aqueous seed extract of Hunteria umbellata ( HU ) were investigated in normal and drug-induced hyperglycaemic rats. In addition, the acute oral toxicity using the preliminary and the main tests of the Up-and-down Procedure according to OECD/OCDE Test Guidelines on Acute Oral Toxicity was conducted. Phytochemical analysis of the aqueous seed extract was also carried out. Results showed that HU caused progressive and significant (p
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Haematopoetic effect of methanol seed extract of Citrus paradisi Macfad (grape fruit) in Wistar rats
Biomedical Research-tokyo, 2008Co-Authors: A.a. AdeneyeAbstract:The present study was undertaken to evaluate the blood-forming effects of (100% methanol seed extract) of Citrus paradisi Macfad in adult Wistar rats for 30 days as a way of evaluat-ing its traditional use in the treatment of blood deficiencies. Acute oral toxicity study was also conducted using limit dose test of the Up and Down Procedure statistical program (AOT425PgmStat, Version 1.0) at a dose of 2000 mg/kg body weight/oral route. Results showed significant (p
Jordan N. Smith - One of the best experts on this subject based on the ideXlab platform.
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Age dependent acute oral toxicity of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and two anaerobic N-nitroso metabolites in deer mice (Peromyscus maniculatus).
Chemosphere, 2007Co-Authors: Jordan N. Smith, Marina A. Espino, George P. CobbAbstract:Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) transforms anaerobically into N-nitroso compounds: hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine (DNX), and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX). Exposure to these N-nitroso metabolites may occur in areas contaminated with explosives, as anaerobic degradation occurs via some bacteria and is one remediation strategy used for RDX. Few papers report acute oral toxicity and none have evaluated age dependent toxicity of RDX or its N-nitroso metabolites. Median lethal dose (LD50) was determined in deer mice (Peromyscus maniculatus) of three age classifications 21 d, 50 d, and 200 d for RDX, MNX, and TNX using the US EPA Up-and-down Procedure (UDP). Hexahydro-1,3,5-trinitro-1,3,5-triazine and N-nitroso metabolites caused similar overt signs of toxicity. Median lethal dose for 21 d deer mice were 136, 181, and 338 mg/kg for RDX, MNX, and TNX, respectively. Median lethal dose for 50 d deer mice were 319, 575, and 338 mg/kg for RDX, MNX, and TNX, respectively. Median lethal dose for 200 d deer mice were 158, 542, and 999 mg/kg for RDX, MNX, and TNX, respectively. These data suggest that RDX is the most potent compound tested, and age dependent toxicity may exist for all compounds and could play a role in RDX and RDX N-nitroso metabolite ecological risk evaluation of terrestrial wildlife at RDX contaminated sites.
