| Sign In to gain access to subscriptions and/or personal tools. |
The Comparative Pathology of the Glycosidase Inhibitors Swainsonine, Castanospermine, and Calystegines A3, B2, and C1 in Mice
1 USDA-ARS, Poisonous Plant Research Laboratory, Logan, Utah, USA Correspondence: Bryan Stegelmeier, Poisonous Plant Research Laboratory, 1150 East 1400 North, Logan, UT 84321; e-mail:bryan.stegelmeier{at}ars.usda.gov.
To study various polyhydroxy-alkaloid glycosidase inhibitors, 16 groups of 3 mice were dosed using osmotic minipumps with swainsonine (0, 0.1, 1, and 10 mg/kg/day), castanospermine, and calystegines A3, B2, and C1 (1, 10, and 100 mg/kg/day). After 28 days, the mice were euthanized, necropsied, and examined using light and electron microscopy. The high-dose swainsonine–treated mice developed neurologic disease with neuro-visceral vacuolation typical of locoweed poisoning. Castanospermine- and calystegines-treated mice were clinically normal; however, high-dose castanospermine–treated mice had thyroid, renal, hepatic, and skeletal myocyte vacuolation. Histochemically, swainsonine- and castanospermine-induced vacuoles contained mannose-rich oligosaccharides. High-dose calystegine A3–treated mice had increased numbers of granulated cells in the hepatic sinusoids. Electron microscopy, lectin histochemistry, and immunohistochemistry suggest these are pit cells (specialized NK cells). Histochemically, the granules contain glycoproteins or oligosaccharides with abundant terminal N-acetylglucosamine residues. Other calystegine-treated mice were histologically normal. These findings indicate that swainsonine produced lesions similar to locoweed, castanospermine caused vacuolar changes with minor changes in glycogen metabolism, and only calystegine A3 produced minimal hepatic changes. These also suggest that in mice calystegines and castanospermine are less toxic than swainsonine, and as rodents are relatively resistant to disease, they are poor models to study such induced storage diseases.
Key Words: swainsonine • castanospermine • calystegine • astragalus • ipomoea • locoweed Abbreviations: PNA, Arachis hypogea • Con-A, Concanavalia ensiformis • SBA, Glycine X 3max • PWM, Phytolacca americana • WGA, Triticum vulgaris • UEA-1, Ulex europaeus • PAS, periodic acid Schiff • H&E, hematoxylin and eosin
Several plants poisonous to livestock have been identified that contain polyhydroxy-alkaloids that inhibit specific cellular glycosidases. For example, swainsonine is found in many locoweeds (certain Astragalus and Oxytropis species) and is a potent inhibitor of lysosomal  -mannosidase and Golgi mannosidase II (Table 1). Purified swainsonine has been shown to reproduce identical disease and lesions to those produced by locoweed in various animal models (James et al., 1991; Stegelmeier et al., 1995). Recently swainsonine has also been identified with mixtures of other glycosidase-inhibiting polyhydroxy-alkaloids in toxic species of Ipomoea, Sida, Solanum, Physalis, and Convolvulus (Asano et al., 1995; Haraguchi et al., 2003; Molyneux et al., 1995). As many of the diseases induced by these plants differ from the lesions and clinical signs produced by swainsonine alone, more information is needed to determine the contribution of swainsonine and co-occurring alkaloids to these intoxications.
Castanospermine, an indolizidine alkaloid, is structurally and functionally similar to swainsonine (Table 1). It was first isolated from the seeds of the Moreton Bay chestnut tree (Castanospermum australe) that causes fatal gastroenteritis with myocardial degeneration and nephrosis in cattle and horses (Molyneux et al., 1990). Castanospermine inhibits -glucosidase and was included in this work for comparison as the calystegines inhibit cellular β-glucosidases. Calystegines were first identified as hydroxylated nortropane alkaloids, varying in both number and substitution pattern of the hydroxy groups, from Calystegia sepium (Goldmann et al., 1990). Subsequently, similar and additional calystegines were identified in Atropa belladonna, Convolvulus arvensis, and various other Solanum, Scopolia, Hyoscyamus, Morus, Datura, Physalis, and Ipomoea species (Asano et al., 1994; Asano et al., 1996; Casteel et al., 1989; Drager et al., 1994; Molyneux et al., 1993; Molyneux et al., 1994). Common calystegines include the trihydroxylated calystegines that are classified as group A, tetrahydroxylated as group B, and pentahydroxylated as group C. As shown in Table 1, some calystegines are potent glycosidase inhibitors with high in vitro affinities. Subsequently, it has been suggested that in vivo they are likely to disrupt intestinal glycosidases, lysosomal function, and glycoprotein processing. However, this has not been demonstrated in an animal model. As some calystegine-containing plants contain mixtures of other toxins, including swainsonine, it has been difficult to definitively prove the role that calystegines play in poisoning. For example, Ipomoea carnea occurs in tropical regions throughout the world. Poisoning has been reported in Brazil, Sudan, India, and Mozambique (Armien et al., 2007; De Blaogh et al., 1999; Idris et al., 1973; Tirkey et al., 1987). Additionally poisoning has been experimentally reproduced by feeding I. carnea to goats, sheep, and cattle (Adam et al., 1973; Armien et al., 2007; Damir et al., 1987; Idris et al., 1973). Mixtures of swainsonine (0.0029%) and calystegines B1, B2, B3, and C1 (0.0045%) have been isolated from Brazilian I. carnea (Armien et al., 2007; Haraguchi et al., 2003). However, the contribution that the calystegines play in Ipomoea toxicity is unknown. Recent studies suggest that the clinical signs and distribution of lesions differ from those reported for swainsonine alone (Armien et al., 2007; Hueza et al., 2005; James et al., 1991; Stegelmeier et al., 1995). Additional work is needed to define calystegine toxicity and determine their role in Ipomoea toxicity. The purpose of this study was to develop a small animal model so that animals could be treated with relatively small amounts of purified alkaloids; to characterize, in a dose response fashion, the lesions of swainsonine, castanospermine, and calystegines A3, B2, and C1; and to compare the reported lesions produced by the whole Ipomoea plant with those produced by these respective purified glycosidase inhibitors.
Glycosidase Inhibitors The individual alkaloids were purified from ground plant material using published techniques (Haraguchi et al., 2003). The purity of the samples was verified at better than 99% purity using GC-MS analysis (Haraguchi et al., 2003; Molyneux et al., 1993). The biological activities of the purified alkaloids were also verified demonstrating similar glycosidase inhibition as those reported using various in vitro enzyme inhibition assays (Haraguchi et al., 2003; Molyneux et al., 1991; Stegelmeier et al., 1995).
Animals
Special Stains and Immunochemistry Immunohistochemistry was done using minor modification of published techniques (Pinard et al., 2006). Briefly, paraffin-embedded tissue sections were deparaffinized, rehydrated, and incubated in antigen retrieval solution (Dako Inc., Carpinteria, CA) for 20 min. Endogenous peroxidase was blocked by incubating in 3% hydrogen peroxide for 15 min, and nonspecific binding was blocked using protein-blocking agent (Dako) washes of 10 min before application of the primary antibody (anti-VWF, 1:1000; anti-alpha 1-antitrypsin, 1:100; pan cytokeratins, 1:100; chromogranin A, 1:1000; chromgranin B, 1:100; PGP9.5, 1:1000; synapthophypin, 1:1000; CD3, 1:1000; CD45, 1:100; Factor 8, 1:1000; vimentin, 1:10; antilysozyme antibody, 1:1000). The primary antibodies (rabbit origin antibodies from Dako and R&D Systems Minneapolis, MN) were allowed to react with the tissue for 30 min at room temperature. Specific binding was detected using an autostainer (Ventana Medical Systems Inc., Tucson, AZ). The label, streptavidin-biotin-immunoperoxidase (Dako), was used for detection. 3,3'-diaminobenzidine was used as substrate (Dako), and the sections were counterstained with Mayer’s hematoxylin. Positive immunohistochemical controls included liver from control mice to which the appropriate antisera were added and negative controls in which the primary antibodies were replaced with homologous nonimmune sera. Tissues were processed for both light and electron microscopy following commonly used techniques. Serial sections of all neurologic sections were also stained with a modified Bodian silver stain and luxol fast blue/periodic acid Schiff stains (Gato, 1987; Yamamoto and Hirano, 1986).
Statistical Analysis
The actual dose each group received was higher than the projected dose for all of the alkaloid groups (Table 2). However, all the differences in the dose were consistent between groups with all animals receiving about 40% more than the projected doses.
There were no significant differences between the weight gains of the different castanospermine or calystegine groups. However, the high-dose swainsonine mice did gain less than controls and all the other groups (P = 0.03); these mice also ate less. The high-dose castanospermine and calystegine groups all tended to have higher daily food consumption (up from 4.7–5.0 g/mouse/day for the control and low-dose groups to 5.3–5.8 g/mouse/day for the high-dose groups). No statistical comparisons were possible as the animals were penned as groups and food consumption is reported as average food consumed or wasted per mouse per day (Table 2). All of the castanospermine, the calystegine, and the low- and medium-dose swainsonine groups appeared to be clinically unaffected by the dose. However, the high-dose swainsonine–treated mice were clinically anxious, easily excited, and slight intention tremors were apparent upon movement. No significant gross lesions were found in mice in any of the treatment groups.
No significant histologic changes were found in any of the control animals or in any animals receiving 0.1 mg swainsonine/kg/day. All of the mice receiving 1.6 mg swainsonine/kg/day and 14.1 mg swainsonine/kg/day mice had vacuolization of the proximal convoluted tubules of the kidney, and the thyroid follicular epithelium (Figure 1a). Lectin stains of these vacuoles stained positive with WGA, Con-A, and PWM (suggestive of increased residues or oligosaccharides containing free
The high swainsonine dose mice also had vacuolation of many of the dendritic cells and macrophages in the spleen, lymph node, thymus, liver, heart, and lung. They also had extensive vacuolation of hepatocytes, pancreatic acinar cells, parietal cells of the stomach, and cells of the salivary gland and prostate gland. Vacuolation was less severe in various neurons and glial cells, especially those of the peripheral ganglia, nuclei in the pons and medulla, and the Purkinje cells (Figure 2).
Only the high-dose castanospermine-treated mice had mild vacuolar changes in the proximal convoluted tubule epithelium and the thyroid follicular epithelium (Figure 1b). These mice also had minimal vacuolation of the periportal hepatocytes. Affected hepatocytes also had increased amounts of diastase-resistant and diastase-sensitive PAS-positive material. Some skeletal myocytes were also vacuolated with increased amounts of PAS-positive material, most likely glycogen. Mice treated with calystegine A3 at 140 mg/kg/day had increased numbers of round to oval granulated cells within hepatic sinusoids (Figure 3a). The granules were large (0.1–0.2 µm) and eosinophilic, and they often seemed to displace the nucleus to the margins of the cell. Lectin histochemistry demonstrated that these granules were positive with WGA and PWM and lightly positive with ConA (Figure 3b). No altered or vacuolar-related staining was detected with the other lectins in any of the calystegine-treated mice. Ultrastructurally the A3-induced granulated cells were flattened along the hepatic sinusoids beneath the endothelial cells and they were often adjacent to Kupffer cells and hepatocytes. Ultrastructurally their cytoplasm was markedly distended with numerous electron-dense granules. The granules were 400–600 A in diameter, homogeneously electro-dense, membrane-bound granules with small numbers of more dense condensates on the margins. Smaller numbers of multivesicular bodies and mitochondria were also present (Figure 3c). Immunohistochemically the granules and cell membranes were negative for antibodies against factor 8, VWF, several pan-cytokeratins, vimentin, chromogranin A and B, synapthophysin, PGP9.5, CD3, and CD45. The granule’s vacuoles were strongly PAS positive, and staining was diastase resistant (Figure 3d). Hepatocytes of these mice were swollen with minimal cytoplasmic vacuolation (Figure 3a). No additional histologic changes were detected in other tissues. No histologic, histochemical, or ultrastructural changes were detected in any of the calystegine B2- or C1-treated mice.
Ipomoea carnea toxicity has been primarily attributed to the toxic effects of swainsonine. However, many portions of the plant contain nearly as much calystegine B2 and C1, with smaller amounts of B1 and B3 (Armien et al., 2007; Haraguchi et al., 2003). The contribution these calystegines play in toxicity is unknown. The lesions of Ipomoea carnea poisoning are similar to locoweed (Astragalus and Oxytropis spp.) and swainsonine poisoning, but the progression and many of the clinical signs are more severe and progressive. Clinical locoweed poisoning is a chronic disease that requires weeks of ingestion for animals to progressively lose condition and develop weakness, trembling, proprioceptive deficits, altered gait, anxiety, changes in demeanor, and reluctance to stand or move. With extended poisoning, animals become emaciated, dehydrated, and recumbent. Most poisoned animals are euthanized, and related mortalities are commonly due to some accident or misadventure (Stegelmeier et al., 1998; Stegelmeier et al., 1999). Ipomoea poisoning progresses rapidly with high reported mortality. In some areas, Ipomoea poisoning is known as "mata cabra" or "goat killer." Reports suggest poisoned animals have seizures and die suddenly. Although the exact cause of these Ipomoea-associated deaths has not been identified, it has been suggested that it is due to swainsonine with the added effect of calystegine poisoning. Under these study conditions, we found that relatively high doses of calystegines B2 and C1 caused no detectable change in mice. These mice were treated with about 140 mg/kg/day with purified calystegine B2 or C1. This dose is more than 60 times higher than the doses associated with induced and clinical Ipomoea poisoning in goats (Armien et al., 2007). These findings suggest that in mice calystegines alone probably contribute little to Ipomoea toxicity directly and that additional toxins or toxin-synergism should be investigated. Only relatively high doses of swainsonine produced neurologic histologic changes in mice similar to those seen in locoweed poisoning of livestock. The dose, histologic changes, and lectin histochemistry are similar to those previously reported in rats and hamsters (Stegelmeier et al., 1995; Stegelmeier et al., 1999; Stegelmeier et al., 2007). These findings support the hypothesis that rodents are relatively resistant to swainsonine toxicity. Most livestock and wildlife species develop significant clinical and histologic lesions at swainsonine doses of 0.4 mg/kg, with durations as short as several weeks (Stegelmeier et al., 1999; Stegelmeier et al., 2007). These doses are nearly 25 times lower than the swainsonine doses required to produce relatively subtle lesions in these mice. This has several implications. It indicates that rodents are poor models of swainsonine-induced neurologic disease. It also has implications for the safety studies of swainsonine, castanospermine, and the calystegines, as swainsonine has been evaluated as an antiviral, antimetastatic, and cancer therapy or therapeutic adjuvant (Goss et al., 1994; Oredipe et al., 2003b; Oredipe et al., 2003a). When the preclinical safety studies were done using rodent models, the risk analyses concerning safety of swainsonine may have been underestimated. Additional work is needed to identify why rodents are less susceptible and to determine if that mechanism can be used to alter toxicity in other species. If rodents are similarly resistant to calystegine toxicity, our findings suggest that rodent infusion models are poor indicators of calystegine toxicity. Similar to our findings of few detectable calystegine-induced histologic or ultrastructural lesions in mice, Hueza et al. were also unable to produce lesions in rats dosed orally with purified calystegine B1–3 and C1 (Hueza et al., 2005). These rats were orally dosed with doses of 3.0 mg/Kg (B1), 2.4 mg/Kg (B2), 1.2 mg/Kg (B3), and 1.8 mg/Kg (C1) for 14 days. We had hypothesized that much higher doses, longer durations, and continuous infusion would produce lesions in mice. This seems not to be the case. Because calystegine isolation is difficult and expensive, our current efforts are to develop a sensitive animal model for calystegine toxicity in small goats or pigs.
As shown in Table 1, many calystegines are potent glycosidase inhibitors with glycosidase affinities similar to those of swainsonine and castanospermine. However, this study suggests that at these doses in mice, they cause minimal clinical or microscopic pathology. Theoretically the calystegines should inhibit cellular Only the high-dose calystegine A3–treated mice had swollen and heavily granulated hepatic sinusoidal cells with mild hepatocellular swelling. The electron-dense granules morphologically resemble secretory granules, and the histologic and ultrastructural location and cellular features suggest these are pit cells. Pit cells are specialized NK cells that are immunophenotypically, morphologically, and functionally different from circulating NK cells. They are named pit cells because of their characteristic granules that resemble the pit in a grape (Luo et al., 2000). Most cells contain around 13 granules. Pit cell granules are generally ~0.3 µm, round, electron-dense, and membrane-bound structures. The dense inclusion in some granules may contain a less dense halo on one side, and there is often a progression of granules with less electron-dense material until they are similar to multivesicular bodies (Wisse et al., 1976). The granules in the calystegine A3–treated mice were about 2 to 3 times larger (0.4–0.6 µm) than normal pit cell granules. They became the predominate ultrastructural feature as they are much larger than mitochondria, Golgi, and multivesicular bodies. The immunohistochemical studies failed to demonstrate immunoreactivity with antibodies to various other endothelial, lymphocyte, macrophage, or epithelial cell markers. There are several NK-lymphocyte-specific antibodies, but none are available for formalin-fixed/paraffin-embedded tissues (Luo et al., 2000). The pit cell vacuoles were diastase resistant, PAS positive. Lectin and chemical histochemistry suggests the vacuoles are filled with glycoproteins or oligosaccharides rich with terminal N-acetylglucosamine residues. Only weakly positive response with ConA (which binds high mannose glucosaccharides), these are different from the mannose-rich glycosaccharides seen in swainsonine-induced vacuoles. Additional studies are needed to better identify and define this cell type and to determine how calystegine A3 treatment alters their function.
Calystegine A3 has been isolated from potatoes (Solanum tuberosum), sweet potatoes (Ipomoea batatas), egg plant (Solanum melongena), and chili peppers (Capsicum frutescens) (Asano et al., 1997). It inhibits rat β-glucosidase and human These findings indicate that swainsonine-treated mice developed clinical and histologic lesions similar to locoism of livestock, but only at relatively high doses. This suggests that mice are similar to other rodents as they are less susceptible to swainsonine intoxication than most livestock. Mice treated with high castanospermine doses developed mild renal, thyroid, hepatic, and skeletal muscle lesions similar to genetic glycogenosis. In contrast, calystegines B2 and C1 similar to those in Ipomea carnea did not induce significant histological lesions in these conditions; calystegine A3 produced minimal hepatic change of unknown importance. These findings suggest that mice are a relatively poor model for calystegine toxicity. The difference in toxicity between swainsonine and the calystegines also suggests that most of the toxicity of plants containing mixtures of these glycoside-inhibiting alkaloids is due to swainsonine.
The authors thank Dr. Matti Kiupel for his immunohistochemical assistance. They also thank Ed Knoppel and Joseph Jacobson for outstanding technical assistance and animal care and Drs. Stephen Lenz, Jeffery O. Hall, and Anthony P. Knight for their review and suggestions to better this work. This research was conducted with the approval and supervision of the Utah State University Animal Care and Use Committee.
Adam, SE, Tartour, G, Obeid, HM, & Idris, OF. (1973). Effects of Ipomoea carnea on the liver and on serum enzymes in young ruminants. J Comp Pathol, 83(4), 531-42[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Alroy, J, Orgad, U, Ucci, AA, & Gavris, VE. (1985). Swainsonine toxicosis mimics lectin histochemistry of mannosidosis. Vet Pathol, 22(4), 311-16[Abstract] Armien, AG, Tokarnia, CH, Vargas Peixoto, P, & Frese, K. (2007). Spontaneous and experimental glycoprotein storage disease of goats induced by Ipomoea carnea subsp fistulosa (Convolvulaceae). Vet Pathol, 44, 170-84 Asano, N, Kato, A, Kizu, H, Matsui, K, Watson, AA, & Nash, RJ. (1996). Calystegine B4, a novel trehalaase inhibitor from Scopolia japonica. Carbohydr Res, 293, 195-204[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Asano, N, Kato, A, Matsui, K, Watson, AA, Nash, RJ, Molyneux, RJ, Hackett, L, Topping, J, & Winchester, B. (1997). The effects of calystegines isolated from edible fruits and vegetables on mammalian liver glycosidases. Glycobiology, 7(8), 1085-8 Asano, N, Kato, A, Oseki, K, Kizu, H, & Matsui, K. (1995). Calystegins of Physalis alkekengi var. francheti (Solanaceae). Structure determination and their glycosidase inhibitory activities. Eur J Biochem, 229(2), 369-76[Web of Science][Medline] [Order article via Infotrieve] Asano, N, Oseki, K, Tomioka, E, Kizu, H, & Matsui, K. (1994). N-containing sugars from Morus alba and their glycosidase inhibitory activities. Carbohydr Res, 259(2), 243-55[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Castagnaro, M. (1990). Lectin histochemistry of the central nervous system in a case of feline alpha-mannosidosis. Res Vet Sci, 49(3), 375-7[Web of Science][Medline] [Order article via Infotrieve] Casteel, SW, Bailey, EM, Camp, BJ, Bridges, CH, Hejtmancik, E, & Ueckert, DN. (1989). The developmental toxicity of an isolate from the plant Solanum dimidiatum (potato-weed) in Syrian golden hamsters. Toxicon, 27(7), 757-62[Medline] [Order article via Infotrieve] Damir, HA, Adam, SE, & Tartour, G. (1987). The effects of Ipomoea carnea on goats and sheep. Vet Hum Toxicol, 29(4), 316-19[Web of Science][Medline] [Order article via Infotrieve] De Blaogh, KKIM, Dimande, AP, Van der Lugt, JJ, Molyneux, RJ, & Naude, TW. (1999). A lysosomal storage disease induced by Ipomoea carnea in goats in Mozambique. J Vet Diagn Invest, 11, 266-73 Drager, B, Funck, C, Hohler, A, Mrachatz, G, Nahrstedt, A, Portsteffen, A, Schaal, A, & Schmidt, R. (1994). Calystegines as a new group of tropane alkaloids in Solanaceae. Plant Cell Tissue Organ Culture, 38, 235-40[CrossRef][Web of Science] Elbein, AD. In James, LF (Ed.). (1989). The effects of plant indolizidine alkaloids and related compounds on glycoprotein processing. Swainsonine and Related Glycosidase Inhibitors (pp.155-87). Ames, IA: Iowa State University Press Gato, N. (1987). Discriminative staining methods for the nervous system: luxol fast blue-periodic acid-Schiff-hematoxylin triple stain and subsidiary stain methods. Stain Technol, 62, 305-15[Web of Science][Medline] [Order article via Infotrieve] Goldmann, A, Message, B, Tepfer, D, Molyneux, RJ, Duclos, O, Boyer, FD, Pan, YT, & Elbein, AD. (1996). Biological activities of the nortropane alkaloid, calystegine B2 and analogs: structure-function relationships. J Nat Prod, 59, 1137-42[CrossRef][Medline] [Order article via Infotrieve] Goldmann, A, Milat, M, Ducrot, P, Lallamand, J, Maille, M, Lepingle, A, Charpin, I, & Tepfer, D. (1990). Tropane derivatives from Calystegia sepium. Phytochemistry, 29, 2125-7[CrossRef][Web of Science] Goss, PE, Baptiste, J, Fernandes, B, Baker, M, & Dennis, JW. (1994). A phase I study of swainsonine in patients with advanced malignancies. Cancer Res, 54(6), 1450-7 Haraguchi, M, Gorniak, SL, Ikeda, K, Minami, Y, Kato, A, Watson, AA, Nash, RJ, Molyneux, RJ, & Asano, N. (2003). Alkaloidal components in the poisonous plant Ipomoea carnea (Convolvulaceae). J Agric Food Chem, 51, 4995-5000[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Hueza, IM, Guerra, JL, Haraguchi, M, Naoki, A, & Gorniak, SL. (2005). The role of alkaloids in Ipomoea carnea toxicosis: a study in rats. Exp Toxicol Pathol, 57(1), 53-8[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Idris, OF, Tartour, G, Adam, SEI, & Obeid, HM. (1973). Toxicity of ipomoea carnea. Trop Anim Health Prod, 5, 119-23[CrossRef] Ikeda, K, Kato, A, Adachi, I, Haraguchi, M, & Asano, N. (2003). Alkaloids from the poisonous plant Ipomoea carnea: effects on intracellular lysosomal glycosidase activities in human lymphoblast cultures. J Agric Food Chem, 51(26), 7642-6[CrossRef][Web of Science][Medline] [Order article via Infotrieve] James, LF, Panter, KE, Broquist, HP, & Hartley, WJ. (1991). Swainsonine-induced high mountain disease in calves. Vet Hum Toxicol, 33(3), 217-19[Web of Science][Medline] [Order article via Infotrieve] Johnson, AE. (1974). Experimental photosensitization and toxicity in sheep produced by Tetradymia glabrata. Can J Comp Med, 38(4), 406-10[Web of Science][Medline] [Order article via Infotrieve] Luo, DZ, Vermijlen, D, Ahishali, B, Triantis, V, Plakoutsi, G, Braet, F, Vanderkerken, K, & Wisse, E. (2000). On the cell biology of pit cells, the liver-specific NK cells 2. World J Gastroenterol, 6(1), 1-11[Web of Science][Medline] [Order article via Infotrieve] Molyneux, RJ, James, LF, Panter, KE, & Ralphs, MH. (1991). Analysis and distribution of swainsonine and related polyhydroxyindolizidine alkaloids by thin layer chromatography. Phytochem Anal, 2, 125-9[Medline] [Order article via Infotrieve] Molyneux, RJ, James, LF, Ralphs, MH, Pfister, JA, Panter, KE, & Nash, RJ. In Colegate, SM (Ed.). (1994). Polyhydroxy alkaloid glycosidase inhibitors from poisonous plants of global distribution; analysis and identification. Plant-associated Toxins: Agricultural, Phytochemical and Ecological Aspects (pp.107-12). Wallingford Oxon, UK: Cab International Molyneux, RJ, McKenzie, RA, Osullivan, BM, & Elbein, AD. (1995). Identification of the glycosidase inhibitors swainsonine and calystegine b 2 in weir vine (ipomoea sp q6 [aff calobra]) and correlation with toxicity. J Nat Prod, 58(6), 878-86[CrossRef][Medline] [Order article via Infotrieve] Molyneux, RJ, Pan, YT, Goldmann, A, Tepfer, DA, & Elbein, AD. (1993). Calystegins, a novel class of alkaloid glycosidase inhibitors. Arch Biochem Biophys, 304(1), 81-8[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Molyneux, RJ, Tropea, JE, & Elbein, AD. (1990). 7-deoxy-6-epi-castanospermine, a trihydroxyindolizidine alkaloid glycosidase inhibitor from Castanospermum australe. J Nat Prod, 53(3), 609-14[CrossRef][Medline] [Order article via Infotrieve] Morgolis, G, & Pickett, JP. (1956). New applications of the luxol fast blue myelin stain. Lab Invest, 5, 459-73[Web of Science][Medline] [Order article via Infotrieve] Oredipe, OA, Furbert-Harris, PM, Laniyan, I, Green, WR, Griffin, WM, & Sridhar, R. (2003a). Mice primed with swainsonine are protected against doxorubicin-induced lethality. Cell Mol Biol, 49(7), 1089-99[Web of Science][Medline] [Order article via Infotrieve] Oredipe, OA, Furbert-Harris, PM, Laniyan, I, Green, WR, White, SL, Olden, K, Parish-Gause, D, Vaughn, T, Griffin, WM, & Sridhar, R. (2003b). Enhanced proliferation of functionally competent bone marrow cells in different strains of mice treated with swainsonine. Int Immunopharmacol, 3(3), 445-55[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Pinard, J, Wagg, CR, Girard, C, Kiupel, M, & Bedard, C. (2006). Histiocytic sarcoma in the tarsus of a cat. Vet Pathol, 43, 1014-17 Selby, LA, Menges, RW, Houser, EC, Flatt, RE, & Case, AA. (1971). Outbreak of swine malformations associated with the wild black cherry, Prunus serotina. Arch Environ Health, 22(4), 496-501[Web of Science][Medline] [Order article via Infotrieve] Stegelmeier, BL, James, LF, Panter, KE, Ralphs, MH, Gardner, DR, Molyneux, RJ, & Pfister, JA. (1999). The pathogenesis and toxicokinetics of locoweed (Astragalus and Oxytropis spp.) poisoning in livestock. J Nat Toxins, 8(1), 35-45[Web of Science][Medline] [Order article via Infotrieve] Stegelmeier, BL, Lee, ST, James, LF, Gardner, DR, Panter, KE, Ralphs, MH, & Pfister, JA. In Panter, KE, Wierenga, TL, & Pfister, JA (Eds.). (2007). The comparative pathology of locoweed poisoning in livestock, wildlife and rodents. Poisonous Plants Global Research and Solutions (pp.359-65). Cambridge, MA: CABI Publishing Stegelmeier, BL, Molyneux, RJ, Elbein, AD, & James, LF. (1995). The lesions of locoweed (Astragalus mollissimus), swainsonine, and castanospermine in rats. Vet Pathol, 32(3), 289-98[Abstract] Stegelmeier, BL, Snyder, PD, James, LF, Panter, KE, Molyneux, RJ, Gardner, DR, Ralphs, MH, & Pfister, JA. In Garland, TR (Ed.). (1998). The immunologic and toxic effects of locoweed (Astragalus lentiginosus) intoxication in cattle. Toxic Plants and Other Natural Toxicants (pp.285-90). Wallingford Oxon, UK: CAB International Tirkey, K, Yadava, KP, Jha, GJ, & Banerjee, NC. (1987). Effect of feeding of Ipomoea carnea leaves on goats. Ind J Anim Sci, 57(8), 863-66 Wisse, E, van’t Noordende, JM, van der, MJ, & Daems, WT. (1976). The pit cell: description of a new type of cell occurring in rat liver sinusoids and peripheral blood. Cell Tissue Res, 173(4), 423-35[Web of Science][Medline] [Order article via Infotrieve] Yamamoto, T, & Hirano, A. (1986). A comparative study of modified Bielschowsky, Bodian and thioflavin S stains on Alzheimer’s neurofibrillary tangles. Neuropathol Appl Neurobiol, 12, 3-9[Web of Science][Medline] [Order article via Infotrieve]
This version was published on July
1, 2008 Toxicologic Pathology, Vol. 36, No. 5,
651-659 (2008)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
|
 |
|
Sign In to gain access to subscriptions and/or personal tools.
Top
Abstract
Introduction
