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Alfredo Pineyrolopez - One of the best experts on this subject based on the ideXlab platform.
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an experimental model of peripheral neuropathy induced in rats by Karwinskia humboldtiana buckthorn fruit
Journal of The Peripheral Nervous System, 2006Co-Authors: Martha E Salazarleal, Viktor J Romerodiaz, Julio Sepulvedasaavedra, Hector R Martinez, Victor Armando Tamezrodriguez, Alfredo Pineyrolopez, M S Flores, Eduardo M Becerraverdin, Maria Victoria BermudezAbstract:Abstract Intoxication by Karwinskia humboldtiana (buckthorn) fruit presents a neurological picture similar to that of Guillain-Barre syndrome. In this report, we describe an experimental animal model of peripheral neuropathy induced by buckthorn fruit. Four groups of Wistar rats received one oral dose of 1.5 g/kg followed by oral doses of 0.5 g/kg at days 3, 7, 10, and 14 of dried and ground buckthorn fruit in aqueous suspension. Rats were sacrificed at 24, 48, 58, and 112 days after initial dose. Treated animals developed progressive paralysis through 58 days, then completely recovered by 112 days. Sciatic nerves showed segmental demyelination and cellular infiltrates until 58 days after exposure and then remyelinating changes at 112 days. This experimental model for peripheral neuropathy is reproducible and easy to handle. Its manipulation is relatively innocuous and allows us to study reversible peripheral nerve damage. This model can be developed in other animal species and may be useful to test new therapies for peripheral neuropathy.
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in vitro metabolism and toxicity assessment of toxin t 514 peroxisomicine a1 of Karwinskia humboldtiana in microsomes and primary cultured hepatocytes
Toxicology in Vitro, 2005Co-Authors: Magdalena Gomezsilva, Lourdes Garzaocanas, V Rivas, Noemi Waksman, Alfredo PineyrolopezAbstract:Abstract T-514 (Peroxisomicine A1) from Karwinskia humboldtiana is a dimeric hydroxyanthracenone with a highly selective cytotoxic effect on tumor cells. We evaluated the metabolism of this compound in two in vitro systems (liver microsomes and hepatocytes) and assessed the cytotoxicity of its metabolites on normal and tumor cells. Microsomes (12.5, 125 and 250 μg of protein/ml) and hepatocytes (1 × 106 cells/ml) were incubated with the toxin (25 μM) for 0.5, 1, 3, 6, 9, 12 and 24 h and the samples were examined using chromatographic analysis and UV spectra. Two metabolites (M1 and M2) were detected in the rat microsomes and one (M1) in the monkey microsomes. The retention times and UV spectra of the peaks were very similar to those of the toxin T-514. M1 was isolated and identified as a mixture of two isomers. The cytotoxicity of the metabolites was evaluated in Chang liver and Hep G2 cells but they did not show the selective cytotoxic effect on tumor cells seen in the original compound.
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the incidence of poisoning by Karwinskia humboldtiana in mexico
Salud Publica De Mexico, 1995Co-Authors: Bermúdez-de Rocha Mv, Victor Armando Tamezrodriguez, F E Lozanomelendez, G Diazcuello, Alfredo PineyrolopezAbstract:: Intoxication produced by Karwinskia humboldtiana presents a neurological picture similar to that of poliomyelitis, Guillain-Barre syndrome or other polyradiculoneuritis with which it is frequently confused. The purpose of this paper is to report the frequency of this intoxication, by means of the antecedent of ingestion of the fruit and the detection of toxins in blood using a thin layer chromatography method. One hundred fifty four samples of cases with acute flaccid paralysis from 18 states of the country were received. The antecedent of ingestion in 56 of them was corroborated and the detection was positive in 50 of these. In 98 patients there was not antecedent of ingestion and detection was negative in 95 of them. We estimated that the sensibility and specificity of detection method are 89% and 96.9% respectively.
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comparison of the hepatotoxicity of toxin t 514 of Karwinskia humboldtiana and its diastereoisomer in primary liver cell cultures
Toxicon, 1994Co-Authors: Lourdes Garzaocanas, O Torresalanis, Waksman N De Torres, Daniel Acosta, T Jiang, Alfredo PineyrolopezAbstract:Toxin T-514 of Karwinskia humboldtiana has been demonstrated to be hepatotoxic in vivo and in vitro. Recently a diastereoisomer of T-514 has been isolated. In the present study we have evaluated and compared the in vitro hepatoxicity of the diastereoisomer of T-514 using primary cultures of rat hepatocytes. Cytotoxicity was evaluated by release of cytoplasmic enzyme lactate dehydrogenase (LDH), and mitochondrial metabolic function (MTT reduction). The diastereoisomer was shown to be almost as hepatoxic in vitro as toxin T-514.
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in vitro selective toxicity of toxin t 514 from Karwinskia humboldtiana buckthorn plant on various human tumor cell lines
Toxicology, 1994Co-Authors: Alfredo Pineyrolopez, Laura Martinez E De Villarreal, Rogerio GonzalezalanisAbstract:Abstract Toxin T-514 is a dimeric anthracenone isolated from the Karwinskia humboldtiana (buckthorn) plant. Its potential anti-neoplastic effect was evaluated in vitro and the results obtained were compared with the effect of other known anti-cancer agents. Normal and malignant continuous cell lines were tested. After a 72-h exposure, neoplastic cells derived from hepatic, pulmonary and colonic tissues were more sensitive to toxin T-514 than normal cells from the corresponding organ. Hepatoma cells and colon adenocarcinoma CT 50 values were μ g/ml. Lung adenocarcinoma, undifferentiated bronchogenic cancer cells and small cell carcinoma CT 50 values were μ g/ml. All benign cell CT 50 levels tested were > 113 μ g/ml. Thin in vitro selective toxicity found with toxin T-514 was also seen with 5-fluorouracil and mitomycin for colon adenocarcinoma and with epidoxorubicin for undifferentiated bronchogenic cancer cells.
Jose L Reyes - One of the best experts on this subject based on the ideXlab platform.
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The ATP levels in kidneys and blood are mainly decreased by acute ingestion of tullidora (Karwinskia humboldtiana)
Toxicon, 2005Co-Authors: Fernando Jaramillo-juárez, María Luisa Rodríguez-vázquez, T. Quezada-tristán, J. Llamas-viramontes, G. Gabriel Ortíz, Juan Muñoz-martínez, Alfredo Feria-velasco, Jose L ReyesAbstract:Our previous acute toxicity studies with Karwinskia humboldtiana (Kh) in rats showed renal hemodynamic changes with a marked increase in the fractional excretion of sodium and morphological damage. To analyse the effects of Kh or ‘tullidora’ on energetic metabolism, a single dose of an oral preparation from the seed fruits was given to Wistar rats (1.25 g/kg). In tullidora-treated rats there was 8% mortality. ATP concentrations in renal tissue decreased significantly (control: 53.85±3.34, tullidora 38.28±5.31 μmol/g fresh tissue, P
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the atp levels in kidneys and blood are mainly decreased by acute ingestion of tullidora Karwinskia humboldtiana
Toxicon, 2005Co-Authors: Fernando Jaramillojuarez, Maria Luisa Rodriguezvazquez, G. Gabriel Ortíz, Alfredo Feriavelasco, J Munozmartinez, T Quezadatristan, J Llamasviramontes, Jose L ReyesAbstract:Our previous acute toxicity studies with Karwinskia humboldtiana (Kh) in rats showed renal hemodynamic changes with a marked increase in the fractional excretion of sodium and morphological damage. To analyse the effects of Kh or ‘tullidora’ on energetic metabolism, a single dose of an oral preparation from the seed fruits was given to Wistar rats (1.25 g/kg). In tullidora-treated rats there was 8% mortality. ATP concentrations in renal tissue decreased significantly (control: 53.85±3.34, tullidora 38.28±5.31 μmol/g fresh tissue, P<0.05). Total blood (54.8±0.96, tullidora: 40.2±1.55 μmol/dL, P<0.01) and haemoglobin-ATP concentrations (3.69±0.12, tullidora: 2.56±0.11 μmol/g, P<0.01) were also significantly diminished. Moreover, the total protein in renal cortex from tullidora-treated rats decreased as compared to control group (control: 71.43±2.88, tullidora: 55.20±4.06 mg/g fresh tissue, P<0.05). In contrast, Na+–K+-ATPase activity in tullidora-treated animals was not different from control rats. These findings might partially explain the acute effects and mortality observed in the Kh treated rats.
Alfredo Piñeyro-lópez - One of the best experts on this subject based on the ideXlab platform.
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Chemistry, Structure and Biological Activity of Anthracenones of the Karwinskia Genus
Studies in natural products chemistry, 2007Co-Authors: Alfredo Piñeyro-lópez, Noemi WaksmanAbstract:Abstract The genus Karwinskia is included in the order Rhamnaceae and comprises 15 different species of trees and shrubs whose habitat goes from the south part of the U.S.A., all Mexico, Central America, North of Colombia, Cuba, Haiti and the Dominican Republic. So far in Mexico 11 of these species have been reported; most of them, as toxic plants. Karwinskia humboldtiana is the most widespread species. The ingestion of its fruits in humans produces a flaccid paralysis similar to the Guillain-BarreA syndrome and poliomyelitis. From the fruits of these plants, besides some hydroxyanthraquinones already reported for other Rhamnaceae, newly dimeric reported hydroxyanthracenones have been shown to be responsible for the aforementioned neuromotor toxic effects. Structure and chemical properties of hydroxyanthracenones were determined along with their biological activity, focusing on animal toxicity, cytotoxicity and their potential effects on celular function. One of these compounds, T 514 (peroxisomicine A1) has demonstrated a selective in vitro cytotoxicity and therefore a patent for its use as an antineoplasic agent was requested and obtained. Roots of Karwinskia sp. have been also studied on the basis of the popular belief that they act as antidote for the intoxication produced by the ingestion of the fruits. In roots, identical compounds as those obtained from the fruits were isolated, as well as other anthracenones not previously described in Karwinskia sp. Dimeric hydroxyanthracenones have been isolated from Cassia sp and the fungi Dermocibes sp and Cortinarius sp by other researchers. Although there are many papers describing different types of pigments isolated from fungi, such descriptions have been for taxonomic aims and not for investigating their biological activity.
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Optimization and validation of an analytical procedure by high-performance liquid chromatography for the quantification of peroxisomicines and isoperoxisomicines
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2003Co-Authors: A. Osorio-perez, Alfredo Piñeyro-lópez, Ma. De La Luz Salazar-cavazos, N. Waksman De TorresAbstract:Abstract Peroxisomicine A1 is a potential antineoplastic substance extracted from plants of the genus Karwinskia. An RP-HPLC–DAD method was developed and validated for the separation and quantification of four isomers of this compound. These isomers coelute in the preparative procedure and are present at a proportion ranging between 3 and 5% in the peroxisomicine A1 purified in the laboratory. The desirability coefficient of the method described here was enhanced 140% with respect to the previously reported method.
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New Synthetic Derivatives from Peroxisomicine A1 and their Biological Activity
Pharmaceutical Biology, 2002Co-Authors: Rosalba Ramírez-durón, Alfredo Piñeyro-lópez, A. Garcia-luna, Lourdes Garza-ocañas, N. Waksman De TorresAbstract:Peroxisomicine A1 (PA1) is a dimeric anthracenone obtained from plants of the genus Karwinskia. Toxicological studies have demonstrated a selective toxicity of peroxisomicine A1 on various human tumor cell lines in vitro. For this reason it has been considered as a possible antineoplastic agent. This article describes the chemical manipulation of this compound with the purpose of finding a possible relationship between the structure and biological activity. Derivatization procedures on the phenolic OH groups, carbonyl group and aromatic ring are presented. Six new compounds were obtained and purified by several chromatographic methods and the pure products were identified and characterized by UV, IR, MS, and 1 H and 13 C NMR. To evaluate the biological activity of the derivatives, the selective cytoxicity of the compounds on normal and neoplastic human liver cells lines and their effect on catalase activity were analyzed. Cytotoxicity of compounds 2 - 5 suggests that phenolic groups are necessary for the ...
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Peroxisomicine A1 (plant toxin-514) affects normal peroxisome assembly in the yeast Hansenula polymorpha.
Toxicon : official journal of the International Society on Toxinology, 1999Co-Authors: Rigoberto Vargas-zapata, J. Sepulveda-saavedra, Alfredo Piñeyro-lópez, Vladimira Torres-gonzález, Karl B. Rechinger, Ineke Keizer-gunnink, Jan A.k.w. Kiel, Marten VeenhuisAbstract:Previously we demonstrated that peroxisomicine A1 (T-514), a plant toxin isolated from Karwinskia species, has a deteriorating effect on the integrity of peroxisomes of methylotrophic yeasts. Here we describe two strains of Hansenula polymorpha, affected in the normal utilization of methanol as sole source of carbon and energy due to peroxisomicine A1 treatment. The two strains isolated (L17 and RV31) grew poorly on methanol, apparently due to malfunctioning of their peroxisomes. Moreover, the cells displayed a high peroxisome turnover rate. We argue that the peroxisomicine A1 induced phenotype of both strains is due to a genomic mutation. Strain L17 was functionally complemented after transformation with a H. polymorpha genomic library. The complementing 2.8 kb DNA fragment did not contain a well-defined ORF and led us to speculate that it may contain regulatory sequences that, when present in multiple copies in the cell, result in a change of expression of specific genes, thus causing restoration of normal methylotrophic growth.
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Effect of peroxisomicine A2 and T 544 of the genus Karwinskia on peroxisomes of Candida boidinii
FEMS microbiology letters, 1998Co-Authors: Ricardo Salazar-aranda, J. Sepulveda-saavedra, Alfredo Piñeyro-lópez, Noemıć Waksman De Torres, Myrthala Moreno-sepúlvedaAbstract:Dimeric anthracenones have been isolated from toxic plants of the genus Karwinskia (Rhamnaceae). T 514 or peroxisomicine A1 is one of the anthracenonic compounds which produce irreversible and selective damage on the peroxisomes of yeast cells in vivo. In this paper we describe the effect of two structurally related anthracenones on cell viability and on the peroxisomes of the methylotrophic yeast Candida boidinii. As has been described for peroxisomicine A1, peroxisomicine A2 and T 544 caused a decrease in the viability of C. boidinii at all concentrations tested, and disruption of the peroxisomal membrane, T 544 showing the strongest effect. In C. boidinii cell death and peroxisomal damage seem to be independent events.
Maria Victoria Bermudez - One of the best experts on this subject based on the ideXlab platform.
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an experimental model of peripheral neuropathy induced in rats by Karwinskia humboldtiana buckthorn fruit
Journal of The Peripheral Nervous System, 2006Co-Authors: Martha E Salazarleal, Viktor J Romerodiaz, Julio Sepulvedasaavedra, Hector R Martinez, Victor Armando Tamezrodriguez, Alfredo Pineyrolopez, M S Flores, Eduardo M Becerraverdin, Maria Victoria BermudezAbstract:Abstract Intoxication by Karwinskia humboldtiana (buckthorn) fruit presents a neurological picture similar to that of Guillain-Barre syndrome. In this report, we describe an experimental animal model of peripheral neuropathy induced by buckthorn fruit. Four groups of Wistar rats received one oral dose of 1.5 g/kg followed by oral doses of 0.5 g/kg at days 3, 7, 10, and 14 of dried and ground buckthorn fruit in aqueous suspension. Rats were sacrificed at 24, 48, 58, and 112 days after initial dose. Treated animals developed progressive paralysis through 58 days, then completely recovered by 112 days. Sciatic nerves showed segmental demyelination and cellular infiltrates until 58 days after exposure and then remyelinating changes at 112 days. This experimental model for peripheral neuropathy is reproducible and easy to handle. Its manipulation is relatively innocuous and allows us to study reversible peripheral nerve damage. This model can be developed in other animal species and may be useful to test new therapies for peripheral neuropathy.
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clinical diagnosis in Karwinskia humboldtiana polyneuropathy
Journal of the Neurological Sciences, 1998Co-Authors: Hector R Martinez, Ricardo A Rangelguerra, Maria Victoria Bermudez, Laura De Leon FloresAbstract:Intoxication by Karwinskia humboldtiana presents a neurological picture similar to that for Guillain-Barre syndrome or other polyradiculoneuropathies. Clinical diagnosis in poisoned humans may be difficult if no evidence of previous fruit ingestion is available. We present our experience in the clinical diagnosis of Karwinskia humboldtiana polyneuropathy, as confirmed by toxin detection in blood. We designed an open trial at the Pediatric Neurology service and included all cases with acute ascending paralysis that were admitted to our hospital in the last two years. In all cases, we performed hematological, immunological and biochemical profiles, CSF analysis including immunological studies, oligoclonal bands and myelin basic protein determinations. Electrodiagnostic studies were performed, including motor conduction velocities, distal latencies, F-wave latency and compound muscle action potential (CAMP) amplitude. The presence of Karwinskia humboldtiana toxins in blood were determined by thin layer chromatography. In six cases, T-514 Karwinskia humboldtiana toxin was detected. These cases had a symmetric motor polyneuropathy with the absence of tendon reflexes and no sensory signs or cranial nerve involvement. Only one patient required assisted ventilation due to bulbar paralysis. In two of these cases, a sural nerve biopsy revealed a segmental demyelination with swelling and phagocytic chambers in Schwann cells and without lymphocytic infiltration. All six cases survived, with complete recovery in five. We conclude that this intoxication is common in Mexico. The availability of toxin detection in blood samples allows the clinician to establish an accurate diagnosis and should be included in the study of children with polyradiculoneuropathy, especially in countries where this poisonous plant grows.
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frecuencia de intoxicacion con Karwinskia humboldtiana en mexico
Salud Publica De Mexico, 1995Co-Authors: Maria Victoria Bermudez, Fabiola Eugenia Lozano, Victor Armando Tamez, Genaro Diaz, Alfredo PineyroAbstract:Ii~toxication produced by Karwinskia humboldtiana preseirts a neurological pichm similar to that of poliomielitis, Guillain-Basre qndrome or otherpolyr.adi...
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experimental acute intoxication with ripe fruit of Karwinskia humboldtiana tullidora in rat guinea pig hamster and dog
Toxicon, 1992Co-Authors: Maria Victoria Bermudez, Noemi Waksman, M. E. Salazar, F. J. Martínez, Alfredo PineyroAbstract:Previous acute toxicity studies with ‘Tullidora’ in mice showed mainly hepatic and pulmonary complications. We tested samples in rat, guinea-pig, hamster and dog, searching for the mechanism of death. A single oral preparation of ripe fruit of Karwinskia humboldtiana was given to all animals. Clinical signs and histopathology were reproduced in all species except dogs. We propose a selective toxicity of the toxins of this fruit to the lungs and liver.
Noemi Waksman - One of the best experts on this subject based on the ideXlab platform.
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Chemistry, Structure and Biological Activity of Anthracenones of the Karwinskia Genus
Studies in natural products chemistry, 2007Co-Authors: Alfredo Piñeyro-lópez, Noemi WaksmanAbstract:Abstract The genus Karwinskia is included in the order Rhamnaceae and comprises 15 different species of trees and shrubs whose habitat goes from the south part of the U.S.A., all Mexico, Central America, North of Colombia, Cuba, Haiti and the Dominican Republic. So far in Mexico 11 of these species have been reported; most of them, as toxic plants. Karwinskia humboldtiana is the most widespread species. The ingestion of its fruits in humans produces a flaccid paralysis similar to the Guillain-BarreA syndrome and poliomyelitis. From the fruits of these plants, besides some hydroxyanthraquinones already reported for other Rhamnaceae, newly dimeric reported hydroxyanthracenones have been shown to be responsible for the aforementioned neuromotor toxic effects. Structure and chemical properties of hydroxyanthracenones were determined along with their biological activity, focusing on animal toxicity, cytotoxicity and their potential effects on celular function. One of these compounds, T 514 (peroxisomicine A1) has demonstrated a selective in vitro cytotoxicity and therefore a patent for its use as an antineoplasic agent was requested and obtained. Roots of Karwinskia sp. have been also studied on the basis of the popular belief that they act as antidote for the intoxication produced by the ingestion of the fruits. In roots, identical compounds as those obtained from the fruits were isolated, as well as other anthracenones not previously described in Karwinskia sp. Dimeric hydroxyanthracenones have been isolated from Cassia sp and the fungi Dermocibes sp and Cortinarius sp by other researchers. Although there are many papers describing different types of pigments isolated from fungi, such descriptions have been for taxonomic aims and not for investigating their biological activity.
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Antimicrobial activity of coupled hydroxyanthracenones isolated from plants of the genus Karwinskia.
Fitoterapia, 2006Co-Authors: Ricardo Salazar, Verónica Rivas, Gloria M. González, Noemi WaksmanAbstract:The in vitro activity of some isolated hydroxyanthracenones belonging to the genus Karwinskia against four bacteria, six filamentous fungi and four yeast are reported. These hydroxyanthracenones were found to possess antimicrobial activity, particularly against Streptococcus pyogenes, Candida albicans, C. boidinii, C. glabrata and Cryptococcus neoformans; minimal inhibitory concentrations range between 16 and 2 μg/ml.
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Isolation and evaluation of the cytotoxic properties of peroxisomicine isomers from Karwinskia parvifolia
Arkivoc, 2005Co-Authors: Verónica Rivas, Gabriel Cuevas, Lourdes Garza, Noemi WaksmanAbstract:A new compound with a peroxisomicine (dimeric hydroxyanthracenone type) structure was isolated from Karwinskia parvifolia and denominated peroxisomicine A4 (PA4). The stereochemistry of the stereogenic centers of this compound and the previously isolated peroxisomicine A3 (PA3, 3) was elucidated using CD, 13 C NMR and 1
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in vitro metabolism and toxicity assessment of toxin t 514 peroxisomicine a1 of Karwinskia humboldtiana in microsomes and primary cultured hepatocytes
Toxicology in Vitro, 2005Co-Authors: Magdalena Gomezsilva, Lourdes Garzaocanas, V Rivas, Noemi Waksman, Alfredo PineyrolopezAbstract:Abstract T-514 (Peroxisomicine A1) from Karwinskia humboldtiana is a dimeric hydroxyanthracenone with a highly selective cytotoxic effect on tumor cells. We evaluated the metabolism of this compound in two in vitro systems (liver microsomes and hepatocytes) and assessed the cytotoxicity of its metabolites on normal and tumor cells. Microsomes (12.5, 125 and 250 μg of protein/ml) and hepatocytes (1 × 106 cells/ml) were incubated with the toxin (25 μM) for 0.5, 1, 3, 6, 9, 12 and 24 h and the samples were examined using chromatographic analysis and UV spectra. Two metabolites (M1 and M2) were detected in the rat microsomes and one (M1) in the monkey microsomes. The retention times and UV spectra of the peaks were very similar to those of the toxin T-514. M1 was isolated and identified as a mixture of two isomers. The cytotoxicity of the metabolites was evaluated in Chang liver and Hep G2 cells but they did not show the selective cytotoxic effect on tumor cells seen in the original compound.
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The absolute configuration of peroxisomicines A1 and A2
Tetrahedron, 2004Co-Authors: Alejandro Pérez, Noemi Waksman, Rosalba Ramirez‐duron, Alfredo Pineyro‐lopez, Matthias Reichert, Gerhard BringmannAbstract:Abstract Peroxisomicine A1 is a potentially antineoplastic compound isolated from the seeds of Karwinskia parvifolia. It is considered as a useful chemotype for the preparation of topoisomerase II targeted anticancer cells. Stereochemically, it is characterized by the presence of two stereocenters and a rotationally hindered and thus likewise stereogenic biaryl axis. In this contribution, the absolute configuration of peroxisomicine A1 and its epimer, peroxisomicine A2, was established by means of a five-step degradative procedure giving the respective R- and S-configured methyl 2-(2′-methyl-5′-oxotetrahydrofuryl)acetates. The configuration of the degradation product was obtained by means of optical rotation, 1H NMR analysis using a chiral displacement reagent, and by experimental and quantum chemical circular dichroism (CD) investigations. Based on the results obtained here and considering our previous work on the relative configuration at centers versus axis of these compounds, peroxisomicine A1 resulted to be the P,3S,3′S-isomer and peroxisomicine A2 the P,3R,3′S-isomer.
