4,682 results on '"Cycloleucine"'
Search Results
2. Comprehensive analysis of aflatoxin B 1 biosynthesis in Aspergillus flavus via transcriptome-wide m 6 A methylome response to cycloleucine.
- Author
-
Liang L, Wang X, Lan H, Wei S, Lei Y, Zhang S, Zhai H, Hu Y, and Lv Y
- Subjects
- Humans, Aspergillus flavus genetics, Aspergillus flavus metabolism, Aflatoxin B1, Transcriptome, Cycloleucine metabolism, Epigenome, Aflatoxins, Liver Neoplasms genetics
- Abstract
Aspergillus flavus and its toxic aflatoxins secondary metabolites contaminate food and grains, posing a severe threat to human health and leading to liver cancer. Here, we demonstrated that cycloleucine blocked aflatoxin B
1 synthesis by inhibiting N6 -methyladenosine (m6 A) methylation modification of messenger RNA (mRNA). m6 A Methylation Immunoprecipitation Sequencing (m6 A MeRIP-Seq)-based comprehensive transcriptome-wide m6 A profiling identified 102 differentially expressed genes that underwent m6 A modification, of which 22 hypermethylated genes were downregulated and 49 hypomethylated genes were upregulated, suggesting a negative correlation between m6 A methylation and gene expression. Notably, cycloleucine inhibited aflatoxin B1 production via multiple targets. The m6 A sites of several key genes involved in the aflatoxin B1 biosynthesis pathway were significantly enriched in the coding sequence and around the stop codon, resulting in their downregulation. Furthermore, m6 A methylation on genes related to the aflatoxin B1 biosynthesis pathway led to reduced mRNA stability. Cycloleucine inhibition of aflatoxin B1 production highlights its potential as an agent for removing mycotoxins in environmental pollution. ENVIRONMENTAL IMPLICATION: Aflatoxins, highly carcinogenic secondary metabolites produced by Aspergillus flavus, frequently contaminate crops such as peanut, corn, wheat and sesame leading to irreversible loss in the quality and yield of agricultural products and posing serious threats to food safety. Aflatoxins has also been linked to developmental delays and liver cancer in humans. In our study, 'monitoring aflatoxin concentrations and its bioaccumulation in organisms' has been conducted. The results demonstrated that aflatoxin production in A. flavus was completely blocked after cycloleucine treatment. Additionally, we demonstrated that inhibition of aflatoxin was linked to N6 -methyladenosine methylation of multiple genes in aflatoxin biosynthesis pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
3. Transcriptome analysis of the inhibitory effect of cycloleucine on myogenesis.
- Author
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Wang Z, Cai D, Li K, Ju X, and Nie Q
- Subjects
- Animals, Muscle Development, Gene Expression Profiling veterinary, Myoblasts, Cell Differentiation, Cycloleucine pharmacology, Chickens
- Abstract
N6-Methyladenosine (m
6 A) has been reported to involve and play an important role in various biological activities but seldom in poultry myogenesis. Cycloleucine usually functions as a nucleic acid methylation inhibitor, the inhibition efficiency of cycloleucine at the m6 A level and corresponding dynamic changes of poultry muscle cells remain unknown. In this study, we aim to find out the effect of cycloleucine on the total N6-Methyladenosine level and its molecular mechanism for regulating myogenesis. A total of 745 differentially expressed genes (DEGs) were obtained by 10 mM, 20 mM, and 30 mM of cycloleucine treatment compared with 0 mM treatment. DEGs in 10 mM cycloleucine were significantly enriched in the biological process of skeletal muscle and satellite cell proliferation and differentiation, DEGs in 20 and 30 mM cycloleucine were enriched in some metabolic and biosynthetic processes. The trend analysis showed that 85% of all DEGs were significantly clustered into 4 files, among them 59% DEGs were dose-dependent and 26% were dose-independent, 52% DEGs were in downtrend and 33% DEGs were in uptrend. Also, the cycloleucine treatment could trigger cell cycle arrest in the G1 phase and depress myoblast cell proliferation and inhibit myotube formation. In conclusion, cycloleucine could continuously reduce the m6 A level of myoblast cells, depress myoblast cell proliferation and inhibit myotube formation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
4. Discovery and Characterization of Pyridoxal 5′-Phosphate-Dependent Cycloleucine Synthases.
- Author
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Abad, Abner N. D., Seshadri, Kaushik, Ohashi, Masao, Delgadillo, David A., de Moraes, Lygia S., Nagasawa, Kyle K., Liu, Mengting, Johnson, Samuel, Nelson, Hosea M., and Tang, Yi
- Published
- 2024
- Full Text
- View/download PDF
5. Effects of exogenous glycine betaine and cycloleucine on photosynthetic capacity, amino acid composition, and hormone metabolism in Solanum melongena L.
- Author
-
Niu, Tianhang, Zhang, Jing, Li, Jing, Gao, Xiaoping, Ma, Hongyan, Gao, Yanqiang, Chang, Youlin, and Xie, Jianming
- Published
- 2023
- Full Text
- View/download PDF
6. Cycloleucine negatively regulates porcine oocyte maturation and embryo development by modulating N6-methyladenosine and histone modifications.
- Author
-
Zhang M, Zhang S, Zhai Y, Han Y, Huang R, An X, Dai X, and Li Z
- Subjects
- Adenosine analogs & derivatives, Animals, Blastocyst, Embryonic Development, In Vitro Oocyte Maturation Techniques veterinary, Oocytes, Swine, Cycloleucine, Histone Code
- Abstract
Maturation of oocytes and early embryo development are regulated precisely by numerous factors at transcriptional and posttranslational levels through precise mechanisms. N6-methyladenosine (m
6 A) is the most common modification in mRNA which regulates RNA metabolism and gene expression. However, the role of RNA m6 A on porcine oocyte maturation and early embryogenesis is largely unknown. Here, we found that oocytes treated with cycloleucine (CL), an RNA m6 A inhibitor, express impaired cumulus expansion, increased production of reactive oxygen species (ROS) in the mitochondria, and delayed maturation of oocytes by disrupting spindle organization and chromosome alignment. Also, CL halted the development of embryos at the 4-cell stage and resulted in low-quality blastocysts. Furthermore, CL treatment decreased the RNA m6 A, H3K4me3, and H3K9me3 levels, but increased the acetylation level of H4K16 during parthenogenetic embryonic development in pigs. Single-cell RNA-seq (scRNA-seq) analysis further revealed that CL treatment dramatically up-regulated the expression of metabolism-related genes (SLC16A1, and MAIG3 etc.) and maternal related genes, including BTG4, WEE2, and BMP15 among others, at the blastocyst stage. Taken together, inhibition of RNA m6 A by CL impaired meiosis of oocytes and early embryonic development of porcine via RNA m6 A methylation, histone modifications, and altering the expression of metabolism-related genes in blastocysts., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
7. Transcriptome analysis of the inhibitory effect of cycloleucine on myogenesis
- Author
-
Zhijun Wang, Danfeng Cai, Kan Li, Xing Ju, and Qinghua Nie
- Subjects
cycloleucine ,N6-Methyladenosine ,myogenesis ,mRNA-Seq ,chicken ,Animal culture ,SF1-1100 - Abstract
N6-Methyladenosine (m6A) has been reported to involve and play an important role in various biological activities but seldom in poultry myogenesis. Cycloleucine usually functions as a nucleic acid methylation inhibitor, the inhibition efficiency of cycloleucine at the m6A level and corresponding dynamic changes of poultry muscle cells remain unknown. In this study, we aim to find out the effect of cycloleucine on the total N6-Methyladenosine level and its molecular mechanism for regulating myogenesis. A total of 745 differentially expressed genes (DEGs) were obtained by 10 mM, 20 mM, and 30 mM of cycloleucine treatment compared with 0 mM treatment. DEGs in 10 mM cycloleucine were significantly enriched in the biological process of skeletal muscle and satellite cell proliferation and differentiation, DEGs in 20 and 30 mM cycloleucine were enriched in some metabolic and biosynthetic processes. The trend analysis showed that 85% of all DEGs were significantly clustered into 4 files, among them 59% DEGs were dose-dependent and 26% were dose-independent, 52% DEGs were in downtrend and 33% DEGs were in uptrend. Also, the cycloleucine treatment could trigger cell cycle arrest in the G1 phase and depress myoblast cell proliferation and inhibit myotube formation. In conclusion, cycloleucine could continuously reduce the m6A level of myoblast cells, depress myoblast cell proliferation and inhibit myotube formation.
- Published
- 2022
- Full Text
- View/download PDF
8. Effects of exogenous glycine betaine and cycloleucine on photosynthetic capacity, amino acid composition, and hormone metabolism in Solanum melongena L.
- Author
-
Tianhang Niu, Jing Zhang, Jing Li, Xiaoping Gao, Hongyan Ma, Yanqiang Gao, Youlin Chang, and Jianming Xie
- Subjects
Medicine ,Science - Abstract
Abstract Although exogenous glycine betaine (GB) and cycloleucine (Cyc) have been reported to affect animal cell metabolism, their effects on plant growth and development have not been studied extensively. Different concentrations of exogenous glycine betaine (20, 40, and 60 mmol L−1) and cycloleucine (10, 20, and 40 mmol L−1), with 0 mmol L−1 as control, were used to investigate the effects of foliar spraying of betaine and cycloleucine on growth, photosynthesis, chlorophyll fluorescence, Calvin cycle pathway, abaxial leaf burr morphology, endogenous hormones, and amino acid content in eggplant. We found that 40 mmol L−1 glycine betaine had the best effect on plant growth and development; it increased the fresh and dry weight of plants, increased the density of abaxial leaf hairs, increased the net photosynthetic rate and Calvin cycle key enzyme activity of leaves, had an elevating effect on chlorophyll fluorescence parameters, increased endogenous indoleacetic acid (IAA) content and decreased abscisic acid (ABA) content, and increased glutamate, serine, aspartate, and phenylalanine contents. However, cycloleucine significantly inhibited plant growth; plant apical dominance disappeared, plant height and dry and fresh weights decreased significantly, the development of abaxial leaf hairs was hindered, the net photosynthetic rate and Calvin cycle key enzyme activities were inhibited, the endogenous hormones IAA and ABA content decreased, and the conversion and utilization of glutamate, arginine, threonine, and glycine were affected. Combined with the experimental results and plant growth phenotypes, 20 mmol L−1 cycloleucine significantly inhibited plant growth. In conclusion, 40 mmol L−1 glycine betaine and 20 mmol L−1 cycloleucine had different regulatory effects on plant growth and development.
- Published
- 2023
- Full Text
- View/download PDF
9. Effects of Cycloleucine in the Nucleus Accumbens Septi on the Elevated plus Maze Test in Rats.
- Author
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Gargiulo API, Acuña A, Gargiulo MML, Gargiulo ÁJM, Gargiulo MCJ, Baiardi GC, Mora S, Lafuente JV, Romanowicz E, Landa AI, Guevara MA, and Gargiulo PÁ
- Subjects
- Animals, Anti-Anxiety Agents administration & dosage, Cycloleucine administration & dosage, Rats, Anti-Anxiety Agents pharmacology, Behavior, Animal drug effects, Cycloleucine pharmacology, Elevated Plus Maze Test, Nucleus Accumbens drug effects, Psychomotor Performance drug effects
- Abstract
Introduction: In recent years, an important number of studies have emphasized the psychopharmacological actions of cycloleucine (1-aminocyclopentanecarboxylic acid) acting on the NR1 subunit (glycine allosteric site) of NMDA (N-methyl-D-aspartic acid) receptor. We studied the effects of its injection in an anxiety test., Methods: The elevated plus maze test was used. Male rats bilaterally cannulated into the nucleus accumbens septi (NAS) were employed. Rats were divided into 5 groups that received either 1 µL injections of saline or cycloleucine (0.5, 1, 2, or 4 µg) 15 min before testing., Results: Time spent in the open arm was significantly increased by cycloleucine treatment with all doses (1 and 2 µg, p < 0.05; 0.5 and 4 µg, p < 0.01), like number of extreme arrivals (0.5 and 1 µg, p < 0.05; 2 µg, p < 0.01; and 4 µg, p < 0.001). Open arm entries were increased by the highest dose only (4 µg, p < 0.01)., Discussion/conclusion: Present results show no difference between all doses in the time spent in the open arm, suggesting an indirect, noncompetitive action of the drug. The increase in extreme arrivals and open arm entries suggests a dose influence in these parameters. We conclude that cycloleucine influence on the NMDA receptors within NAS leads to anxiolytic-like effects and behavioral disinhibition, which once more confirms the involvement of NAS in anxiety processing., (© 2020 S. Karger AG, Basel.)
- Published
- 2020
- Full Text
- View/download PDF
10. Multicentered hydrogen bonding in 1-[(1-deoxy-β-d-fructopyranos-1-yl)azaniumyl]cyclopentanecarboxylate (`d-fructose-cycloleucine')
- Author
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Valeri V. Mossine, Charles L. Barnes, and Thomas P. Mawhinney
- Subjects
crystal structure ,fructosamine ,Amadori rearrangement ,cycloleucine ,hydrogen bonding ,Hirshfeld surface analysis ,Crystallography ,QD901-999 - Abstract
The title compound, C12H21NO7, (I), is conformationally unstable; the predominant form present in its solution is the β-pyranose form (74.3%), followed by the β- and α-furanoses (12.1 and 10.2%, respectively), α-pyranose (3.4%), and traces of the acyclic carbohydrate tautomer. In the crystalline state, the carbohydrate part of (I) adopts the 2C5 β-pyranose conformation, and the amino acid portion exists as a zwitterion, with the side chain cyclopentane ring assuming the E9 envelope conformation. All heteroatoms are involved in hydrogen bonding that forms a system of antiparallel infinite chains of fused R33(6) and R33(8) rings. The molecule features extensive intramolecular hydrogen bonding, which is uniquely multicentered and involves the carboxylate, ammonium and carbohydrate hydroxy groups. In contrast, the contribution of intermolecular O...H/H...O contacts to the Hirshfeld surface is relatively low (38.4%), as compared to structures of other d-fructose-amino acids. The 1H NMR data suggest a slow rotation around the C1—C2 bond in (I), indicating that the intramolecular heteroatom contacts survive in aqueous solution of the molecule as well.
- Published
- 2019
- Full Text
- View/download PDF
11. Analysis of metabolite differences between South Korean and Chinese yellow goosefish (Lophius litulon) using capillary electrophoresis time-of-flight mass spectrometry.
- Author
-
Yang J, Shin J, Kim H, Sim Y, Cha E, and Yang J
- Subjects
- Animals, Electrophoresis, Capillary, Republic of Korea, China, Cycloleucine analysis, Fishes metabolism, Muscles chemistry, Muscles metabolism
- Abstract
The yellow goosefish is a benthic fish that belongs to the family Lophiidae and order Lophiiformes and is distributed in the Yellow and East China Seas. This study aimed to distinguish between yellow goosefish from different geographical origins by analyzing their metabolites. Capillary electrophoresis time-of-flight mass spectrometry was used to analyze metabolite profiles in the muscle tissues of yellow goosefish to distinguish between Korean and Chinese yellow goosefish. In total, 271 putative metabolites were extracted using 50% acetonitrile in water. Principal component analysis and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to distinguish different geographical origins using the metabolite profiles obtained. The R
2 and Q2 values of the OPLS-DA model were 0.856 and 0.695, respectively, indicating that the model was well-fitted and had good predictability. The heat map revealed that nucleic acid and amino compounds differed between the Korean and Chinese fish, and the variable importance in the projection scores obtained from OPLS-DA showed that there were geographical differences in the primary metabolites (5'-methylthioadenosine, adenosine, uridine 5-diphosphate, guanosine 5-diphosphate, urea, homocarnosine, O-acetylcarnitine, cycloleucine, cycloleucine S-adenosylmethionine, S-adenosylhomocysteine, ethanolamine, myo-inositol 1-phosphate), which were identified as potential candidate biomarkers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)- Published
- 2023
- Full Text
- View/download PDF
12. Triple-Methyl Blockade With Recombinant Methioninase, Cycloleucine, and Azacitidine Arrests a Pancreatic Cancer Patient-Derived Orthotopic Xenograft Model.
- Author
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Sugisawa N, Yamamoto J, Han Q, Tan Y, Tashiro Y, Nishino H, Inubushi S, Hamada K, Kawaguchi K, Unno M, Bouvet M, and Hoffman RM
- Subjects
- Animals, Cell Proliferation drug effects, DNA Methylation drug effects, Fibrosis, Humans, Mice, Nude, Necrosis, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Proof of Concept Study, Time Factors, Tumor Burden, Xenograft Model Antitumor Assays, Mice, Antineoplastic Combined Chemotherapy Protocols pharmacology, Azacitidine pharmacology, Carbon-Sulfur Lyases pharmacology, Cycloleucine pharmacology, Methionine metabolism, Pancreatic Neoplasms drug therapy
- Abstract
Objectives: Methionine addiction is a fundamental and general hallmark of cancer caused by enhanced methyl flux. In the present study, we effected a novel methionine-methylation blockade to target a patient-derived orthotopic xenograft model of pancreatic cancer., Methods: The pancreatic cancer patient-derived orthotopic xenograft mouse models were randomized into 6 groups of 8 mice each and treated for 2 weeks: untreated control; azacitidine; oral recombinant methioninase (o-rMETase); o-rMETase plus cycloleucine; o-rMETase plus cycloleucine plus azacitidine (triple-methyl blockade therapy); and gemcitabine (positive control)., Results: Triple-methyl blockade therapy arrested tumor growth (mean relative tumor volume, 1.03 [standard deviation, 0.36]) and was significantly more effective compared with azacitidine (P = 0.0001); o-rMETase (P = 0.007); or o-rMETase plus cycloleucine (P = 0.04). Gemcitabine alone also inhibited but did not arrest tumor growth (mean relative tumor volume, 1.50 [standard deviation, 0.30]). The percentage of cancer cells that were negative for 5-methylcytosine staining in immunohistochemistry, indicating reduction of DNA methylation, increased with triple-methyl blockade therapy (37.5%), compared with gemcitabine (1.8%); o-rMETase (2.8%); azacitidine (9.0%); or o-rMETase plus cycloleucine (10.6%)., Conclusions: This new concept of triple-methyl blockade therapy has clinical potential for pancreatic cancer, which is currently a recalcitrant disease., Competing Interests: The authors declare no conflicts of interest. AntiCancer, Inc uses patient-derived orthotopic xenograft models for contract research. Q.H. and Y.T. are employees of AntiCancer, Inc. N.S., J.Y., Y.T., H.N., S.I., K.H., and R.M.H. are or were unsalaried associates of AntiCancer, Inc., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
13. Cycloleucine negatively regulates porcine oocyte maturation and embryo development by modulating N6-methyladenosine and histone modifications
- Author
-
Yu Han, Yanhui Zhai, Meng Zhang, Rong Huang, Xinglan An, Sheng Zhang, Xiangpeng Dai, and Ziyi Li
- Subjects
Adenosine ,Swine ,Embryonic Development ,chemistry.chemical_compound ,Food Animals ,Gene expression ,medicine ,Animals ,Cycloleucine ,Small Animals ,Gene ,Messenger RNA ,Equine ,Chemistry ,RNA ,Oocyte ,In Vitro Oocyte Maturation Techniques ,Cell biology ,Histone Code ,Blastocyst ,medicine.anatomical_structure ,Oocytes ,Spindle organization ,Animal Science and Zoology ,N6-Methyladenosine - Abstract
Maturation of oocytes and early embryo development are regulated precisely by numerous factors at transcriptional and posttranslational levels through precise mechanisms. N6-methyladenosine (m6A) is the most common modification in mRNA which regulates RNA metabolism and gene expression. However, the role of RNA m6A on porcine oocyte maturation and early embryogenesis is largely unknown. Here, we found that oocytes treated with cycloleucine (CL), an RNA m6A inhibitor, express impaired cumulus expansion, increased production of reactive oxygen species (ROS) in the mitochondria, and delayed maturation of oocytes by disrupting spindle organization and chromosome alignment. Also, CL halted the development of embryos at the 4-cell stage and resulted in low-quality blastocysts. Furthermore, CL treatment decreased the RNA m6A, H3K4me3, and H3K9me3 levels, but increased the acetylation level of H4K16 during parthenogenetic embryonic development in pigs. Single-cell RNA-seq (scRNA-seq) analysis further revealed that CL treatment dramatically up-regulated the expression of metabolism-related genes (SLC16A1, and MAIG3 etc.) and maternal related genes, including BTG4, WEE2, and BMP15 among others, at the blastocyst stage. Taken together, inhibition of RNA m6A by CL impaired meiosis of oocytes and early embryonic development of porcine via RNA m6A methylation, histone modifications, and altering the expression of metabolism-related genes in blastocysts.
- Published
- 2022
14. Comprehensive analysis of aflatoxin B1 biosynthesis in Aspergillus flavus via transcriptome-wide m6A methylome response to cycloleucine
- Author
-
Liang, Liuke, primary, Wang, Xiaoyan, additional, Lan, Haier, additional, Wei, Shan, additional, Lei, Yang, additional, Zhang, Shuaibing, additional, Zhai, Huanchen, additional, Hu, Yuansen, additional, and Lv, Yangyong, additional
- Published
- 2023
- Full Text
- View/download PDF
15. Effects of Cycloleucine in the Nucleus Accumbens Septi on the Elevated plus Maze Test in Rats
- Author
-
Pascual Angel Gargiulo, Andres Acuña, Adriana Inés Landa, Sergio Mora, Esteban Alejandro Romanowicz, Gustavo Baiardi, Augusto Pascual Ítalo Gargiulo, Marcos C. J. Gargiulo, José Vicente Lafuente, Manuel Alejandro Guevara, Ángel José Martín Gargiulo, and Mercedes Maria Lucrecia Gargiulo
- Subjects
medicine.medical_specialty ,Elevated plus maze ,medicine.medical_treatment ,Nucleus accumbens ,Nucleus Accumbens ,Elevated Plus Maze Test ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Cycloleucine ,Receptor ,Saline ,Biological Psychiatry ,Behavior, Animal ,Chemistry ,Rats ,030227 psychiatry ,Psychiatry and Mental health ,Neuropsychology and Physiological Psychology ,Endocrinology ,Anti-Anxiety Agents ,Disinhibition ,Glycine ,NMDA receptor ,medicine.symptom ,Psychomotor Performance ,030217 neurology & neurosurgery - Abstract
Introduction: In recent years, an important number of studies have emphasized the psychopharmacological actions of cycloleucine (1-aminocyclopentanecarboxylic acid) acting on the NR1 subunit (glycine allosteric site) of NMDA (N-methyl-D-aspartic acid) receptor. We studied the effects of its injection in an anxiety test. Methods: The elevated plus maze test was used. Male rats bilaterally cannulated into the nucleus accumbens septi (NAS) were employed. Rats were divided into 5 groups that received either 1 µL injections of saline or cycloleucine (0.5, 1, 2, or 4 µg) 15 min before testing. Results: Time spent in the open arm was significantly increased by cycloleucine treatment with all doses (1 and 2 µg, p < 0.05; 0.5 and 4 µg, p < 0.01), like number of extreme arrivals (0.5 and 1 µg, p < 0.05; 2 µg, p < 0.01; and 4 µg, p < 0.001). Open arm entries were increased by the highest dose only (4 µg, p < 0.01). Discussion/Conclusion: Present results show no difference between all doses in the time spent in the open arm, suggesting an indirect, noncompetitive action of the drug. The increase in extreme arrivals and open arm entries suggests a dose influence in these parameters. We conclude that cycloleucine influence on the NMDA receptors within NAS leads to anxiolytic-like effects and behavioral disinhibition, which once more confirms the involvement of NAS in anxiety processing.
- Published
- 2020
16. Effects of Exogenous Glycine Betaine and Cycloleucine on Photosynthetic Capacity, Amino Acid Composition, and Hormone Metabolism in Solanum melongena L
- Author
-
Niu, Tianhang, primary, Zhang, Jing, additional, Li, Jing, additional, Gao, Xiaoping, additional, Ma, Hongyan, additional, Gao, Yanqiang, additional, Chang, Youlin, additional, and Xie, Jianming, additional
- Published
- 2022
- Full Text
- View/download PDF
17. A morphological study of the effects of cycloleucine on the central and peripheral nervous systems of the mouse
- Author
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Lee, Chin-Cheng Michael
- Subjects
612.8 - Abstract
Cycloleucine (CL) is a very potent inhibitor of S-adenosyl methionine transferase causing a rapid decline in CNS S-adenosyl methionine levels and increase in methionine in the nervous system. CL interrupts the transmethylation reaction in the CNS similar to that caused by deficiency of vitamin B12 or folic acid. CL was administered as a single dose intraperitoneally (2mg/g body weight) to mice of varying ages (21 days - 5 months). The 21 day old mice given CL 2mg/g body weight showed evidence of toxicity within 24 hours and thereafter developed progressive muscle weakness and ataxia. Animals did not survive longer than 1 week. Light and electron microscopic examination o f the central and peripheral nervous systems, from 12 hours to 7 days post-injection showed that intramyelinic vacuolation developed in the white matter of brain and cord within 12 hours but no myelin vacuolation occurred in peripheral nerves. Axonal lesions in the distal parts of motor nerves occurred within 1 2 - 2 4 hours resulting in degeneration of intramuscular nerve fibres and terminals. Motor end-plates became denervated. There was no degeneration of motor or sensory nerves in the muscle spindles. Later there was evidence of axonal degeneration in tibial and sciatic nerves. Many dorsal root ganglion cells became vacuolated or necrotic three days after administration of CL and numerous degenerated fibres were noted in the white matter of the spinal cord, especially in funiculus gracilis. The intramyelinic vacuolation in the white matter of brain and cord persisted and became more severe during the course of the experiment. In adult mice (6 weeks - 5 months) the pathology consisted mainly of distal motor axonal degeneration which developed at 1 - 2 days. Only slight intramyelinic vacuolation in white matter was noted. At 3 days later, numerous degenerated fibres were seen in the posterior columns of cervical cord, especially in the funiculus gracilis. In a second series of experiments valine (3 mg/g body weight) was given every 12 hours for 6 doses beginning either 24 or 48 hours after CL. Valine (VL) is a very effective antidote against cycloleucine and reversed its toxicity. The intramyelinic vacuolation disappeared from the white matter in the CNS leaving little residual pathology. Regenerating axons and remyelinated fibres were found in previously degenerated distal peripheral nerves and denervated motor end-plates. The reinnervation took place more rapidly in animals given VL from 24 hours after CL than 48 hours after CL. In conclusion it can be stated that CL causes a distal motor axonopathy and sensory ganglion cell necrosis in addition to the previously reported myelinic vacuolation in the CNS. The mechanism of toxicity of CL is likely to be related to the failure of transmethylation processes affecting particularly myelin basic protein and perhaps membrane turnover at active sites of transmitter release such as the neuromuscular junction.
- Published
- 1991
18. Effects of Exogenous Glycine Betaine and Cycloleucine on Photosynthetic Capacity, Amino Acid Composition, and Hormone Metabolism in Solanum melongena L
- Author
-
Tianhang Niu, Jing Zhang, Jing Li, Xiaoping Gao, Hongyan Ma, Yanqiang Gao, Youlin Chang, and Jianming Xie
- Abstract
Although exogenous glycine betaine and cycloleucine have been reported to affect animal cell metabolism, their effects on plant growth and development have not been studied extensively. Different concentrations of exogenous glycine betaine (20, 40, and 60 mmol L− 1) and cycloleucine (10, 20, and 40 mmol L− 1), with 0 mmol L− 1 as control, were used to investigate the effects of foliar spraying of betaine and cycloleucine on growth, photosynthesis, chlorophyll fluorescence, Calvin cycle pathway, abaxial leaf burr morphology, endogenous hormones, and amino acid content in eggplant. We found that 40 mmol L− 1 glycine betaine had the best effect on plant growth and development; it increased the fresh and dry weight of plants, increased the density of abaxial leaf hairs, increased the net photosynthetic rate and Calvin cycle key enzyme activity of leaves, had an elevating effect on chlorophyll fluorescence parameters, increased endogenous IAA content and decreased ABA content, and increased glutamate, serine, aspartate, and phenylalanine contents. However, cycloleucine significantly inhibited plant growth; plant apical dominance disappeared, plant height and dry and fresh weights decreased significantly, the development of abaxial leaf hairs was hindered, the net photosynthetic rate and Calvin cycle key enzyme activities were inhibited, the endogenous hormones IAA and ABA content decreased, and the conversion and utilization of glutamate, arginine, threonine, and glycine were affected. Combined with the experimental results and plant growth phenotypes, 20 mmol L− 1 cycloleucine significantly inhibited plant growth. In conclusion, 40 mmol L− 1 glycine betaine and 20 mmol L− 1 cycloleucine had different regulatory effects on plant growth and development.
- Published
- 2022
19. The effects of cycloleucine on nerve, muscle, and neuromuscular transmission in the mouse : an electrophysiological and morphological study
- Author
-
Edwards, Jonathan Paul
- Subjects
616.8 - Abstract
Cycloleucine (CL) is a synthetic annino acid which inhibits the vitamin B12/folate dependent methyl-transfer reaction. A single dose of CL (2mg/g body weight) was administered intraperitoneally to 21-day-old and adult mice. Animals were allowed to survive for between 12 hours and 7 days. The 21-day-old mice showed paralysis of the hindlimbs within 24 hours, whereas this symptom became apparent in the adult mice at 48 hours. In the adult mice the twitch and tetanic responses of extensor digitorum longus (Edl) and soleus evoked by neural stimulation fell dramatically within 24 hours. In both the 21-day-old and the adult mice intracellular recordings made at 24 hours in soleus and Edl revealed that a significant number of end-plates were denervated, while other end-plates demonstrated intermittent failures in transmission and end- plate potentials (epps) with prolonged latencies. End-plates with abnormally high frequencies of miniature end-plate potentials (mepps) were commonly encountered in soleus and Edl, of 21-day-old mice at 12 hours, and in the adult mice at 24 hours. Morphological abnormalities in both the intramuscular nerves and the neuromuscular junctions of soleus and Edl were seen in both the young and adult mice at 24 hours. These abnormalities included areas of electron lucent axoplasm and swollen degenerative mitochondria and nerve terminals lacking synaptic vesicles. The innervation of proximal muscles was unaffected at this time. Over the next 2-3 days further reductions in the number of soleus and Edl fibres demonstrating mepps or epps occurred in both young and adult mice. The muscle spindles in soleus were found to be both functionally and structurally intact. At 7 days a limited recovery of function occurred in both soleus and Edl of young and adult mice. In biceps brachii of young mice, however, denervated end-plates and abnormally high mepp frequencies were found at 7 days. It is suggested that the distal motor axonopathy induced by CL is caused by the failure of the methyl-transfer pathway which leads to abnormalities in the phospholipid composition of the axolemma at the neuromuscular junction. These changes are believed to cause an increase in microviscosity of the axolemma and hence a decrease in efficiency of ion channels/pumps which are responsible for maintaining electrochemical gradients essential for the structural and functional integrity of the neuromuscular junction.
- Published
- 1993
20. Triple-Methyl Blockade With Recombinant Methioninase, Cycloleucine, and Azacitidine Arrests a Pancreatic Cancer Patient-Derived Orthotopic Xenograft Model
- Author
-
Sachiko Inubushi, Michiaki Unno, Kei Kawaguchi, Jun Yamamoto, Yuying Tan, Qinghong Han, Yoshihiko Tashiro, Robert M. Hoffman, Michael Bouvet, Hiroto Nishino, Kazuyuki Hamada, and Norihiko Sugisawa
- Subjects
Time Factors ,Endocrinology, Diabetes and Metabolism ,Azacitidine ,Mice, Nude ,Proof of Concept Study ,03 medical and health sciences ,chemistry.chemical_compound ,Necrosis ,0302 clinical medicine ,Endocrinology ,Methionine ,Pancreatic cancer ,Antineoplastic Combined Chemotherapy Protocols ,Internal Medicine ,medicine ,Animals ,Humans ,Cycloleucine ,Cell Proliferation ,Hepatology ,business.industry ,Cancer ,DNA Methylation ,medicine.disease ,Fibrosis ,Xenograft Model Antitumor Assays ,Gemcitabine ,Blockade ,Tumor Burden ,Pancreatic Neoplasms ,Carbon-Sulfur Lyases ,chemistry ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Immunohistochemistry ,030211 gastroenterology & hepatology ,business ,medicine.drug - Abstract
Objectives Methionine addiction is a fundamental and general hallmark of cancer caused by enhanced methyl flux. In the present study, we effected a novel methionine-methylation blockade to target a patient-derived orthotopic xenograft model of pancreatic cancer. Methods The pancreatic cancer patient-derived orthotopic xenograft mouse models were randomized into 6 groups of 8 mice each and treated for 2 weeks: untreated control; azacitidine; oral recombinant methioninase (o-rMETase); o-rMETase plus cycloleucine; o-rMETase plus cycloleucine plus azacitidine (triple-methyl blockade therapy); and gemcitabine (positive control). Results Triple-methyl blockade therapy arrested tumor growth (mean relative tumor volume, 1.03 [standard deviation, 0.36]) and was significantly more effective compared with azacitidine (P = 0.0001); o-rMETase (P = 0.007); or o-rMETase plus cycloleucine (P = 0.04). Gemcitabine alone also inhibited but did not arrest tumor growth (mean relative tumor volume, 1.50 [standard deviation, 0.30]). The percentage of cancer cells that were negative for 5-methylcytosine staining in immunohistochemistry, indicating reduction of DNA methylation, increased with triple-methyl blockade therapy (37.5%), compared with gemcitabine (1.8%); o-rMETase (2.8%); azacitidine (9.0%); or o-rMETase plus cycloleucine (10.6%). Conclusions This new concept of triple-methyl blockade therapy has clinical potential for pancreatic cancer, which is currently a recalcitrant disease.
- Published
- 2020
21. Multicentered hydrogen bonding in 1-[(1-deoxy-β-d-fructopyranos-1-yl)azaniumyl]cyclopentanecarboxylate ('d-fructose-cycloleucine')
- Author
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Thomas P. Mawhinney, Charles L. Barnes, and Valeri V. Mossine
- Subjects
0301 basic medicine ,crystal structure ,Stereochemistry ,Heteroatom ,Amadori rearrangement ,010403 inorganic & nuclear chemistry ,Ring (chemistry) ,cycloleucine ,01 natural sciences ,cycloleucine ,Research Communications ,03 medical and health sciences ,chemistry.chemical_compound ,Side chain ,Hirshfeld surface analysis ,General Materials Science ,Aqueous solution ,fructosamine ,Crystallography ,Hydrogen bond ,Chemistry ,General Chemistry ,Condensed Matter Physics ,hydrogen bonding ,Tautomer ,0104 chemical sciences ,030104 developmental biology ,QD901-999 ,Zwitterion ,Proton NMR - Abstract
The molecule is a zwitterion and features a strong multicentered intramolecular hydrogen bonding involving the carboxyl, amino, and anomeric hydroxyl groups. It adopts the 2 C 5 β-pyranose conformation, which also the dominant form present in its solution., The title compound, C12H21NO7, (I), is conformationally unstable; the predominant form present in its solution is the β-pyranose form (74.3%), followed by the β- and α-furanoses (12.1 and 10.2%, respectively), α-pyranose (3.4%), and traces of the acyclic carbohydrate tautomer. In the crystalline state, the carbohydrate part of (I) adopts the 2 C 5 β-pyranose conformation, and the amino acid portion exists as a zwitterion, with the side chain cyclopentane ring assuming the E 9 envelope conformation. All heteroatoms are involved in hydrogen bonding that forms a system of antiparallel infinite chains of fused R 3 3(6) and R 3 3(8) rings. The molecule features extensive intramolecular hydrogen bonding, which is uniquely multicentered and involves the carboxylate, ammonium and carbohydrate hydroxy groups. In contrast, the contribution of intermolecular O⋯H/H⋯O contacts to the Hirshfeld surface is relatively low (38.4%), as compared to structures of other d-fructose-amino acids. The 1H NMR data suggest a slow rotation around the C1—C2 bond in (I), indicating that the intramolecular heteroatom contacts survive in aqueous solution of the molecule as well.
- Published
- 2019
22. m6a Methylation Inhibition by Cycloleucine Impaired Porcine Oocyte Meiosis and Early Embryonic Development via Remodeling Histone Modifications and Altering Metabolism Related Gene Expression in Blastocysts
- Author
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Xinglan An, Xiangpeng Dai, Sheng Zhang, Rong Huang, Yanhui Zhai, Meng Zhang, Yu Han, and Ziyi Li
- Subjects
chemistry.chemical_compound ,Cycloleucine ,Histone ,chemistry ,Embryogenesis ,biology.protein ,Oocyte meiosis ,Metabolism ,Methylation ,Related gene ,Biology ,Cell biology - Abstract
BackgroundOocytes maturation and early embryo development were regulated precisely by a series of factors at transcriptional and posttranslational levels. N6-methyladenosine (m6A) is the most prevalent modification in mRNA as a crucial regulator in RNA metabolism and gene regulation. However, the role of m6A on porcine oocyte maturation and early embryogenesis is largely unknown. ResultsHere, we found that oocytes treated with cycloleucine (CL), an inhibitor of m6A, could impair cumulus expansion, elevate mitochondrial reactive oxygen species (ROS) concentration and decreased oocytes maturation which partially caused by disturbed spindle organization and chromosomes alignment. Moreover, our results indicated that the CL treated parthenogenetic embryos arrested at 4-cell stage and showed worse blastocyst quality. CL treatment not only decreased the methylation levels of nucleic acid, H3K4me3 and H3K9me3, while increased the acetylation level of H4K16 during parthenogenetic embryos development in pigs. Furthermore, single cell RNA-seq (scRNA-seq) analysis indicated that CL treatment dramatically elevated the expression of metabolism-related (SLC16A1 and MAIG3 etc.) and maternal related (BTG4, WEE2 and BMP15 etc.) genes at blastocyst stage. ConclusionsTaken together, we found that m6A methylation inhibition by CL impaired porcine oocyte meiosis and early embryonic development via remodeling histone modifications and altering metabolism related gene expression in blastocysts.
- Published
- 2020
23. Molecular Umbrella as a Nanocarrier for Antifungals.
- Author
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Skwarecki AS, Martynow D, Milewska MJ, and Milewski S
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- Antifungal Agents pharmacology, Candida albicans drug effects, Candida glabrata drug effects, Cholic Acid chemistry, Cycloleucine chemistry, Drug Carriers administration & dosage, Drug Carriers pharmacology, Erythrocytes drug effects, Hemolytic Agents chemistry, Hemolytic Agents pharmacology, Humans, Microbial Sensitivity Tests, Molecular Structure, Structure-Activity Relationship, Antifungal Agents administration & dosage, Antifungal Agents chemistry, Cycloleucine analogs & derivatives, Drug Carriers chemistry
- Abstract
A molecular umbrella composed of two O -sulfated cholic acid residues was applied for the construction of conjugates with cispentacin, containing a "trimethyl lock" (TML) or o -dithiobenzylcarbamoyl moiety as a cleavable linker. Three out of five conjugates demonstrated antifungal in vitro activity against C. albicans and C. glabrata but not against C. krusei , with MIC
90 values in the 0.22-0.99 mM range and were not hemolytic. Antifungal activity of the most active conjugate 24c , containing the TML-pimelate linker, was comparable to that of intact cispentacin. A structural analogue of 24c , containing the Nap-NH2 fluorescent probe, was accumulated in Candida cells, and TML-containing conjugates were cleaved in cell-free extract of C. albicans cells. These results suggest that a molecular umbrella can be successfully applied as a nanocarrier for the construction of cleavable antifungal conjugates.- Published
- 2021
- Full Text
- View/download PDF
24. AntiCancer Inc. Reports Findings in Xenografts (Triple-methyl Blockade With Recombinant Methioninase, Cycloleucine, and Azacitidine Arrests a Pancreatic Cancer Patient-derived Orthotopic Xenograft Model)
- Subjects
Methylation -- Research -- Analysis -- Models ,Cancer patients -- Research -- Models -- Analysis ,Cancer -- Care and treatment ,Physical fitness -- Models -- Research -- Analysis ,Pancreatic cancer -- Research ,Health - Abstract
2021 JAN 30 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Current study results on Biotechnology - Xenografts have been published. According to [...]
- Published
- 2021
25. Cadmium inhibition of basolateral solute fluxes in rabbit renal tubules and the nature of cycloleucine uptake.
- Author
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Foulkes EC and Blanck S
- Subjects
- Animals, Biological Transport drug effects, Cycloleucine pharmacology, Kidney Cortex drug effects, Kidney Cortex metabolism, Kidney Tubules metabolism, Leucine pharmacology, Male, Probenecid pharmacology, Rabbits, p-Aminohippuric Acid metabolism, p-Aminohippuric Acid pharmacology, Cadmium toxicity, Cycloleucine pharmacokinetics, Kidney Tubules drug effects
- Abstract
The objective of this investigation was to determine whether Cd inhibition of amino acid transport across basolateral (BL) cell membranes in renal tubules results from a direct toxic action at that site. The concentration ratio (R) of cycloleucine in cell water/arterial plasma at steady state in nonfiltering rabbit kidneys consistently exceeded 1.0, thus confirming the active nature of BL amino acid uptake. BL cycloleucine extrusion, though down the concentration gradient, has previously been shown to be greatly slowed in Cd-poisoned animals; nevertheless, R remained unchanged. Active uptake and passive extrusion of cycloleucine must therefore be equally sensitive to Cd, a fact strongly suggesting an indirect action of the metal on BL solute transfer. This hypothesis is strengthened by the observation that R for paraaminohippurate (PAH), another solute actively accumulated across BL membranes, also remained unaffected by Cd poisoning. The reduction in R(PAH) by the direct transport inhibitor probenecid served as positive control. The additional finding that R(cycloleucine) is also depressed by probenecid, as well as by excess PAH, indicates some overlap in substrate specificities of the two carrier systems. The systems are not identical, however, as can be deduced from the observation that L-leucine affected only transport of cycloleucine, not that of PAH.
- Published
- 1991
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26. Cycloleucine fluxes during rat vasa recta and loop microinfusions in vivo and loop microperfusions in vitro
- Author
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Pannabecker, T.L., Völker, K., Silbernagl, S., and Dantzler, W.H.
- Published
- 2000
- Full Text
- View/download PDF
27. m6a Methylation Inhibition by Cycloleucine Impaired Porcine Oocyte Meiosis and Early Embryonic Development via Remodeling Histone Modifications and Altering Metabolism Related Gene Expression in Blastocysts
- Author
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Zhang, Meng, primary, Zhang, Sheng, additional, Zhai, Yanhui, additional, Han, Yu, additional, Huang, Rong, additional, An, Xinglan, additional, Dai, Xiangpeng, additional, and Li, Ziyi, additional
- Published
- 2020
- Full Text
- View/download PDF
28. Mettl3 Mediated m6A Methylation Involved in Epithelial-Mesenchymal Transition by Targeting SOCS3/STAT3/SNAI1 in Cigarette Smoking-Induced COPD
- Author
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Zhang Y, Wang L, Yan F, Yang M, Gao H, and Zeng Y
- Subjects
inflammation ,copd ,merip–sequencing ,cycloleucine ,Diseases of the respiratory system ,RC705-779 - Abstract
Yaping Zhang,1,* Lixing Wang,1,* Furong Yan,1 Meili Yang,2 Hongzhi Gao,1 Yiming Zeng3 1Clinical Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, People’s Republic of China; 2Department of Neurology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yaping Zhang, Clinical Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, No. 34 Zhongshan North Road, Licheng District, Quanzhou, Fujian, People’s Republic of China, Email icesuri@126.comPurpose: Persistent inflammation and epithelial-mesenchymal transition are essential pathophysiological processes in chronic obstructive pulmonary disease (COPD) and involve airway remodeling. m6A methylation modification was discovered to play an important role in various diseases. Nevertheless, the regulatory role of m6A methylation has not yet been investigated in cigarette smoking-induced COPD. The study aims to explore the regulatory role of m6A methylation in cigarette smoking-induced COPD.Patients and Methods: In this study, two Gene Expression Omnibus (GEO) datasets were first utilized to analyze the expression profiles of m6A RNA methylation regulators in COPD. We then established a cell model of COPD by exposing human bronchial epithelial cells (HBECs) to cigarette smoke extract (CSE) in vitro and detected the expression of m6A writer Mettl3 and EMT phenotype markers. RNA interference, cycloleucine, RT-qPCR, western blot, MeRIP-sequencing, and cell migration assay were performed to investigate the potential effect of Mettl3 on the EMT process in CSE-induced HBECs.Results: Our results showed that Mettl3 expression was significantly elevated in cigarette smoking-induced COPD patients and in a cellular model of COPD. Furthermore, Mettl3 silence and cycloleucine treatment inhibited the EMT process of HBECs caused by CSE. Mechanically, Mettl3 silence weakens the m6A methylation of SOCS3 mRNA to enhance the protein expression of SOCS3, inhibiting CSE-induced SOCS3/STAT3/SNAI1 signaling and EMT processes in HBECs.Conclusion: Our study inferred that Mettl3-mediated m6A RNA methylation modification modulates CSE-induced EMT by targeting SOCS3 mRNA and ultimately serves as a crucial regulator in the emergence of COPD. This conclusion reinforces the regulatory role of m6A methylation in COPD.Keywords: inflammation, COPD, MeRIP–sequencing, cycloleucine
- Published
- 2023
29. [Effect of cycloleucine on renal uptake of dibasic amino acids and cystine].
- Author
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Moatti N, Lemonnier A, and Barthon F
- Subjects
- Amino Acids urine, Animals, Humans, Kidney drug effects, Rats, Amino Acids metabolism, Arginine metabolism, Cycloleucine metabolism, Cystine metabolism, Kidney metabolism, Lysine metabolism, Ornithine metabolism
- Abstract
Cycloleucinead ministration (a synthetic amino acid) to rats produces a selective hyperaminoaciduria bearing on dibasic amino acids (lysine, arginine, ornithine) and cystine. Interference of cycloleucine with tubular reabsorption of these amino acids was studied "in vitro", using rat kidney cortex slices. When dibasic amino acids and cystine are at physiological concentrations, the data indicate that cycloleucine decreases their intracellular accumulation. However, effect of cycloleucine "in vitro" is not specific whatsoever its concentration; similar results are obtained with neutral amino acids such as alpha-alanine and valine. Inhibitory effects are not modified by the presence of several amino acids in the incubation medium. The results are interpreted as evidence for a dissociation between "in vitro" cellular accumu-lation and "in vivo" transepithelial transport.
- Published
- 1976
30. Depletion of S-adenosyl-l-methionine with cycloleucine potentiates cytochrome P450 2E1 toxicity in primary rat hepatocytes.
- Author
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Zhuge J and Cederbaum AI
- Subjects
- Animals, Apoptosis drug effects, Cell Survival, Cells, Cultured, Chlormethiazole pharmacology, Cytochrome P-450 CYP2E1 Inhibitors, Glutathione metabolism, Hepatocytes drug effects, Methionine Adenosyltransferase antagonists & inhibitors, Methionine Adenosyltransferase metabolism, Pyrazoles toxicity, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species metabolism, Cycloleucine pharmacology, Cytochrome P-450 CYP2E1 metabolism, Hepatocytes cytology, Hepatocytes metabolism, S-Adenosylmethionine metabolism
- Abstract
S-Adenosyl-l-methionine (SAM) is the principal biological methyl donor. Methionine adenosyltransferase (MAT) catalyzes the only reaction that generates SAM. Hepatocytes were treated with cycloleucine, an inhibitor of MAT, to evaluate whether hepatocytes enriched in cytochrome P450 2E1 (CYP2E1) were more sensitive to a decline in SAM. Cycloleucine decreased SAM and glutathione (GSH) levels and induced cytotoxicity in hepatocytes from pyrazole-treated rats (with an increased content of CYP2E1) to a greater extent as compared to hepatocytes from saline-treated rats. Apoptosis caused by cycloleucine in pyrazole hepatocytes appeared earlier and was more pronounced than control hepatocytes and could be prevented by incubation with SAM, glutathione reduced ethyl ester and antioxidants. The cytotoxicity was prevented by treating rats with chlormethiazole, a specific inhibitor of CYP2E1. Cycloleucine induced greater production of reactive oxygen species (ROS) in pyrazole hepatocytes than in control hepatocytes, and treatment with SAM, Trolox, and chlormethiazole lowered ROS formation. In conclusion, lowering of hepatic SAM levels produced greater toxicity and apoptosis in hepatocytes enriched in CYP2E1. This is due to elevated ROS production by CYP2E1 coupled to lower levels of hepatoprotective SAM and GSH. We speculate that such interactions e.g. induction of CYP2E1, decline in SAM and GSH may contribute to alcohol liver toxicity.
- Published
- 2007
- Full Text
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31. Cycloleucine (1-amino-cyclopentane carboxylic acid): Tubular reabsorption and inhibitory effect on amino acid transport in the rat kidney (microperfusion experiments)
- Author
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Silbernagl, Stefan
- Published
- 1975
- Full Text
- View/download PDF
32. Microperfusion study of the kinetics of reabsorption of cycloleucine in early and late segments of the proximal convolution of the rat nephron
- Author
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Lingard, J. M., Györy, A. Z., and Young, J. A.
- Published
- 1975
- Full Text
- View/download PDF
33. Multicentered hydrogen bonding in 1-[(1-deoxy-β-D-fructopyranos-1-yl)azaniumyl]cyclopentanecarboxylate ('D-fructose-cycloleucine').
- Author
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Mossine, Valeri V., Barnes, Charles L., and Mawhinney, Thomas P.
- Subjects
- *
HYDROGEN bonding , *ZWITTERIONS , *AQUEOUS solutions , *AMINO acids , *CARBOHYDRATES - Abstract
The title compound, C12H21NO7, (I), is conformationally unstable; the predominant form present in its solution is the β-pyranose form (74.3%), followed by the β- and α-furanoses (12.1 and 10.2%, respectively), α-pyranose (3.4%), and traces of the acyclic carbohydrate tautomer. In the crystalline state, the carbohydrate part of (I) adopts the ²C5 β-pyranose conformation, and the amino acid portion exists as a zwitterion, with the side chain cyclopentane ring assuming the E9 envelope conformation. All heteroatoms are involved in hydrogen bonding that forms a system of antiparallel infinite chains of fused R3³(6) and R3³(8) rings. The molecule features extensive intramolecular hydrogen bonding, which is uniquely multicentered and involves the carboxylate, ammonium and carbohydrate hydroxy groups. In contrast, the contribution of intermolecular O···H/H···O contacts to the Hirshfeld surface is relatively low (38.4%), as compared to structures of other D-fructose-amino acids. The ¹H NMR data suggest a slow rotation around the C1--C2 bond in (I), indicating that the intramolecular heteroatom contacts survive in aqueous solution of the molecule as well. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
34. Depletion of S-adenosyl-l-methionine with cycloleucine potentiates cytochrome P450 2E1 toxicity in primary rat hepatocytes
- Author
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Jian Zhuge and Arthur I. Cederbaum
- Subjects
S-Adenosylmethionine ,Cell Survival ,Biophysics ,Apoptosis ,Biochemistry ,Article ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Animals ,Cycloleucine ,Molecular Biology ,Cells, Cultured ,chemistry.chemical_classification ,Reactive oxygen species ,Cytochrome P-450 CYP2E1 ,Methionine Adenosyltransferase ,Glutathione ,CYP2E1 ,Molecular biology ,Rats ,Cytochrome P-450 CYP2E1 Inhibitors ,chemistry ,Toxicity ,Hepatocytes ,Pyrazoles ,Trolox ,Reactive Oxygen Species ,Chlormethiazole - Abstract
S-Adenosyl-l-methionine (SAM) is the principal biological methyl donor. Methionine adenosyltransferase (MAT) catalyzes the only reaction that generates SAM. Hepatocytes were treated with cycloleucine, an inhibitor of MAT, to evaluate whether hepatocytes enriched in cytochrome P450 2E1 (CYP2E1) were more sensitive to a decline in SAM. Cycloleucine decreased SAM and glutathione (GSH) levels and induced cytotoxicity in hepatocytes from pyrazole-treated rats (with an increased content of CYP2E1) to a greater extent as compared to hepatocytes from saline-treated rats. Apoptosis caused by cycloleucine in pyrazole hepatocytes appeared earlier and was more pronounced than control hepatocytes and could be prevented by incubation with SAM, glutathione reduced ethyl ester and antioxidants. The cytotoxicity was prevented by treating rats with chlormethiazole, a specific inhibitor of CYP2E1. Cycloleucine induced greater production of reactive oxygen species (ROS) in pyrazole hepatocytes than in control hepatocytes, and treatment with SAM, Trolox, and chlormethiazole lowered ROS formation. In conclusion, lowering of hepatic SAM levels produced greater toxicity and apoptosis in hepatocytes enriched in CYP2E1. This is due to elevated ROS production by CYP2E1 coupled to lower levels of hepatoprotective SAM and GSH. We speculate that such interactions e.g. induction of CYP2E1, decline in SAM and GSH may contribute to alcohol liver toxicity.
- Published
- 2007
35. Enhancement by glucocorticoid deficiency of the increase in cycloleucine accumulation induced in rat thymocytes by triiodothyronine
- Author
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Etzkorn, J. R., Hopkins, P., Gluckin, D., Gray, J., Goldfine, I. D., and Ingbar, S. H.
- Published
- 1979
- Full Text
- View/download PDF
36. Evaluation of β-Amino Acid Replacements in Protein Loops: Effects on Conformational Stability and Structure.
- Author
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Mortenson DE, Kreitler DF, Thomas NC, Guzei IA, Gellman SH, and Forest KT
- Subjects
- Cycloleucine chemistry, Models, Molecular, Molecular Structure, Protein Stability, Temperature, Amino Acids chemistry, Cycloleucine analogs & derivatives, Proteins chemistry
- Abstract
β-Amino acids have a backbone that is expanded by one carbon atom relative to α-amino acids, and β residues have been investigated as subunits in protein-like molecules that adopt discrete and predictable conformations. Two classes of β residue have been widely explored in the context of generating α-helix-like conformations: β
3 -amino acids, which are homologous to α-amino acids and bear a side chain on the backbone carbon adjacent to nitrogen, and residues constrained by a five-membered ring, such the one derived from trans-2-aminocyclopentanecarboxylic acid (ACPC). Substitution of α residues with their β3 homologues within an α-helix-forming sequence generally causes a decrease in conformational stability. Use of a ring-constrained β residue, however, can offset the destabilizing effect of α→β substitution. Here we extend the study of α→β substitutions, involving both β3 and ACPC residues, to short loops within a small tertiary motif. We start from previously reported variants of the Pin1 WW domain that contain a two-, three-, or four-residue β-hairpin loop, and we evaluate α→β replacements at each loop position for each variant. By referral to the ϕ,ψ angles of the native structure, one can choose a stereochemically appropriate ACPC residue. Use of such logically chosen ACPC residues enhances conformational stability in several cases. Crystal structures of three β-containing Pin1 WW domain variants show that a native-like tertiary structure is maintained in each case., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2018
- Full Text
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37. Combination Methionine-methylation-axis Blockade: A Novel Approach to Target the Methionine Addiction of Cancer
- Author
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Higuchi, Takashi, Han, Qinghong, Sugisawa, Norihiko, Yamamoto, Jun, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Igarashi, Kentaro, Bouvet, Michael, Singh, Shree Ram, Tsuchiya, Hiroyuki, and Hoffman, Robert M
- Subjects
Brain Disorders ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Animals ,Disease Models ,Animal ,Humans ,Methionine ,Methylation ,Mice ,Mice ,Nude ,Neoplasms ,methionine addiction ,methionine restriction ,methionine-methylation-axis blockade ,decitabine ,cycloleucine ,MAT2A ,soft-tissue sarcoma ,PDOX ,Immunology ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Background/aimCancers are selectively sensitive to methionine (MET) restriction (MR) due to their addiction to MET which is overused for elevated methylation reactions. MET addiction of cancer was discovered by us 45 years ago. MR of cancer results in depletion of S-adenosylmethionine (SAM) for transmethylation reactions, resulting in selective cancer-growth arrest in the late S/G2-phase of the cell cycle. The aim of the present study was to determine if blockade of the MET-methylation axis is a highly-effective strategy for cancer chemotherapy.Materials and methodsIn the present study, we demonstrated the efficacy of MET-methylation-axis blockade using MR by oral-recombinant methioninase (o-rMETase) combined with decitabine (DAC), an inhibitor of DNA methylation, and an inhibitor of SAM synthesis, cycloleucine (CL). We determined a proof-of-concept of the efficacy of the MET-methylation-axis blockade on a recalcitrant undifferentiated/unclassified soft-tissue sarcoma (USTS) patient-derived orthotopic xenograft (PDOX) mouse model.ResultsThe o-rMETase-CL-DAC combination regressed the USTS PDOX with extensive cancer necrosis.ConclusionThe new concept of combination MET-methylation-axis blockade is effective and can now be tested on many types of recalcitrant cancer.
- Published
- 2021
38. Comparison of doxorubicin with cycloleucine in the treatment of sarcomas.
- Author
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Savlov ED, MacIntyre JM, Knight E, and Wolter J
- Subjects
- Adult, Clinical Trials as Topic, Cycloleucine administration & dosage, Cycloleucine adverse effects, Doxorubicin administration & dosage, Doxorubicin adverse effects, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Prognosis, Amino Acids therapeutic use, Cycloleucine therapeutic use, Doxorubicin therapeutic use, Sarcoma drug therapy, Soft Tissue Neoplasms drug therapy
- Abstract
In this patient series, doxorubicin and cycloleucine at a dose of 300 mg/kg both show response rates in the treatment of advanced soft tissue sarcomas of about 15%. Lower doses of cycloleucine (200 mg/kg) yielded less toxicity but were less effective against the sarcomas (6% response rate, three of 51 patients). There were no complete responses with cycloleucine and there were three with doxorubicin. Survival times for patients receiving doxorubicin were significantly longer than those of patients receiving cycloleucine at doses of 300 mg/kg (P less than 0.001) or 200 mg/kg (P = 0.02). The estimated survival times were 29 weeks for doxorubicin and 21 (300 mg/kg) and 18 (200 mg/kg) weeks for cycloleucine. Toxic effects due to cycloleucine were excessive, with severe thrombocytopenia and central nervous system depression being the most prominent.
- Published
- 1981
39. Effects of cycloleucine on macrophages and on experimental allergic encephalomyelitis.
- Author
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Levine S and Sowinski R
- Subjects
- Adrenalectomy, Animals, Brain cytology, Brain immunology, Cycloleucine administration & dosage, Cycloleucine therapeutic use, Cyclophosphamide pharmacology, Drug Administration Schedule, Encephalomyelitis, Autoimmune, Experimental immunology, Freund's Adjuvant pharmacology, Hydrocortisone pharmacology, Immunization, Passive, Inflammation drug therapy, Lymph Nodes immunology, Macrophages immunology, Male, Organ Size drug effects, Rats, Rats, Inbred Lew, Spleen anatomy & histology, Thymus Gland anatomy & histology, Amino Acids pharmacology, Cycloleucine pharmacology, Encephalomyelitis, Autoimmune, Experimental prevention & control, Macrophages drug effects
- Published
- 1977
- Full Text
- View/download PDF
40. Hydrophilic and Cell-Penetrable Pyrrolidinyl Peptide Nucleic Acid via Post-synthetic Modification with Hydrophilic Side Chains.
- Author
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Pansuwan H, Ditmangklo B, Vilaivan C, Jiangchareon B, Pan-In P, Wanichwecharungruang S, Palaga T, Nuanyai T, Suparpprom C, and Vilaivan T
- Subjects
- Cell Membrane Permeability, Cycloleucine chemical synthesis, Cycloleucine metabolism, Dipeptides chemical synthesis, Dipeptides metabolism, HEK293 Cells, Humans, Hydrophobic and Hydrophilic Interactions, Peptide Nucleic Acids chemical synthesis, Peptide Nucleic Acids metabolism, Permeability, Pyrrolidines chemical synthesis, Pyrrolidines metabolism, Solubility, Temperature, Cycloleucine analogs & derivatives, Dipeptides chemistry, Peptide Nucleic Acids chemistry, Pyrrolidines chemistry
- Abstract
Peptide nucleic acid (PNA) is a nucleic acid mimic in which the deoxyribose-phosphate was replaced by a peptide-like backbone. The absence of negative charge in the PNA backbone leads to several unique behaviors including a stronger binding and salt independency of the PNA-DNA duplex stability. However, PNA possesses poor aqueous solubility and cannot directly penetrate cell membranes. These are major obstacles that limit in vivo applications of PNA. In previous strategies, the PNA can be conjugated to macromolecular carriers or modified with positively charged side chains such as guanidinium groups to improve the aqueous solubility and cell permeability. In general, a preformed modified PNA monomer was required. In this study, a new approach for post-synthetic modification of PNA backbone with one or more hydrophilic groups was proposed. The PNA used in this study was the conformationally constrained pyrrolidinyl PNA with prolyl-2-aminocyclopentanecarboxylic acid dipeptide backbone (acpcPNA) that shows several advantages over the conventional PNA. The aldehyde modifiers carrying different linkers (alkylene and oligo(ethylene glycol)) and end groups (-OH, -NH
2 , and guanidinium) were synthesized and attached to the backbone of modified acpcPNA by reductive alkylation. The hybrids between the modified acpcPNAs and DNA exhibited comparable or superior thermal stability with base-pairing specificity similar to those of unmodified acpcPNA. Moreover, the modified apcPNAs also showed the improvement of aqueous solubility (10-20 folds compared to unmodified PNA) and readily penetrate cell membranes without requiring any special delivery agents. This study not only demonstrates the practicality of the proposed post-synthetic modification approach for PNA modification, which could be readily applied to other systems, but also opens up opportunities for using pyrrolidinyl PNA in various applications such as intracellular RNA sensing, specific gene detection, and antisense and antigene therapy.- Published
- 2017
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41. Selective Targeting by a Mechanism-Based Inactivator against Pyridoxal 5'-Phosphate-Dependent Enzymes: Mechanisms of Inactivation and Alternative Turnover.
- Author
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Mascarenhas R, Le HV, Clevenger KD, Lehrer HJ, Ringe D, Kelleher NL, Silverman RB, and Liu D
- Subjects
- 4-Aminobutyrate Transaminase chemistry, 4-Aminobutyrate Transaminase metabolism, Aspartate Aminotransferases chemistry, Aspartate Aminotransferases genetics, Aspartate Aminotransferases metabolism, Binding Sites, Catalytic Domain, Crystallography, X-Ray, Cycloleucine chemistry, Cycloleucine metabolism, Cycloleucine pharmacology, Databases, Chemical, Databases, Protein, Enzyme Inhibitors chemistry, Enzyme Inhibitors metabolism, Escherichia coli Proteins antagonists & inhibitors, Escherichia coli Proteins chemistry, Escherichia coli Proteins genetics, Escherichia coli Proteins metabolism, Humans, Ligands, Molecular Conformation, Ornithine-Oxo-Acid Transaminase chemistry, Ornithine-Oxo-Acid Transaminase genetics, Ornithine-Oxo-Acid Transaminase metabolism, Protein Conformation, Pyridoxal Phosphate chemistry, Pyridoxamine chemistry, Pyridoxamine metabolism, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Structural Homology, Protein, Substrate Specificity, 4-Aminobutyrate Transaminase antagonists & inhibitors, Aspartate Aminotransferases antagonists & inhibitors, Cycloleucine analogs & derivatives, Enzyme Inhibitors pharmacology, Models, Molecular, Ornithine-Oxo-Acid Transaminase antagonists & inhibitors, Pyridoxal Phosphate metabolism
- Abstract
Potent mechanism-based inactivators can be rationally designed against pyridoxal 5'-phosphate (PLP)-dependent drug targets, such as ornithine aminotransferase (OAT) or γ-aminobutyric acid aminotransferase (GABA-AT). An important challenge, however, is the lack of selectivity toward other PLP-dependent, off-target enzymes, because of similarities in mechanisms of all PLP-dependent aminotransferase reactions. On the basis of complex crystal structures, we investigate the inactivation mechanism of OAT, a hepatocellular carcinoma target, by (1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP), a known inactivator of GABA-AT. A crystal structure of OAT and FCP showed the formation of a ternary adduct. This adduct can be rationalized as occurring via an enamine mechanism of inactivation, similar to that reported for GABA-AT. However, the crystal structure of an off-target, PLP-dependent enzyme, aspartate aminotransferase (Asp-AT), in complex with FCP, along with the results of attempted inhibition assays, suggests that FCP is not an inactivator of Asp-AT, but rather an alternate substrate. Turnover of FCP by Asp-AT is also supported by high-resolution mass spectrometry. Amid existing difficulties in achieving selectivity of inactivation among a large number of PLP-dependent enzymes, the obtained results provide evidence that a desirable selectivity could be achieved, taking advantage of subtle structural and mechanistic differences between a drug-target enzyme and an off-target enzyme, despite their largely similar substrate binding sites and catalytic mechanisms.
- Published
- 2017
- Full Text
- View/download PDF
42. The evolution of an experimental distal motor axonopathy. Physiological studies of changes in neuromuscular transmission caused by cycloleucine, an inhibitor of methionine adenosyltransferase.
- Author
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Edwards JP, Lee CC, and Duchen LW
- Subjects
- Animals, Electric Conductivity, Female, Male, Membrane Potentials, Mice, Mice, Inbred BALB C, Motor Endplate ultrastructure, Muscle Spindles physiopathology, Muscle, Skeletal drug effects, Muscle, Skeletal physiopathology, Muscles drug effects, Muscles physiopathology, Neuromuscular Junction ultrastructure, Peripheral Nervous System Diseases metabolism, Peripheral Nervous System Diseases pathology, Axons, Cycloleucine pharmacology, Methionine Adenosyltransferase antagonists & inhibitors, Motor Endplate drug effects, Motor Endplate physiopathology, Neuromuscular Junction drug effects, Neuromuscular Junction physiopathology, Peripheral Nervous System Diseases physiopathology, Synaptic Transmission drug effects
- Abstract
Cycloleucine (CL), a synthetic amino acid is known to cause degeneration of motor nerve terminals. This paper describes the changes in neuromuscular transmission, the morphology of motor end-plates and the responses of muscle spindles after a single dose of CL was administered to weanling and adult mice. Animals were allowed to survive for between 12 h and 7 days. Twitch and tetanic responses of muscles stimulated through their nerves fell dramatically within 24 h in both young and adult mice and intracellular recordings revealed that a large proportion of end-plates in calf muscles became denervated, whilst at other end-plates intermittent failure of transmission and end-plate potentials (EPPs) with prolonged latency were demonstrated. End-plates with an abnormally high frequency of miniature end-plate potentials (mEPPs) were found in young mice at 12 h, and in the adult mice at 24 h. Morphological abnormalities in intramuscular nerves and nerve terminals included areas of electron lucent axoplasm, swollen degenerative mitochondria and loss of synaptic vesicles. Over the next 2-3 days further reductions occurred in the number of end-plates at which mEPPs or EPPs could be demonstrated. At 7 days a limited recovery of function occurred in distal muscles but proximal muscles, hitherto unaffected, now began to show abnormalities of transmission. Muscle spindles were found to be both functionally and structurally intact. It is suggested that this acute distal motor axonopathy is due to abnormalities in phospholipid composition of the axolemma of motor nerve terminals resulting from the failure of methyl-transfer pathways. These abnormalities in phospholipid composition might cause an increase in microviscosity of the axolemma and hence a decrease in efficiency of ion channels and pumps responsible for maintaining electrochemical gradients, essential for the structural and functional integrity of the neuromuscular junction.
- Published
- 1994
- Full Text
- View/download PDF
43. Multicentered hydrogen bonding in 1-[(1-deoxy-β-D-fructopyranos-1-yl)azaniumyl]cyclopentanecarboxylate (`D-fructose-cycloleucine')
- Author
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Mossine, Valeri V., primary, Barnes, Charles L., additional, and Mawhinney, Thomas P., additional
- Published
- 2019
- Full Text
- View/download PDF
44. Volume of renal cortical cytoplasm in rabbits, and basolateral transport gradients of cycloleucine and p-aminohippurate.
- Author
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Foulkes EC and Blanck S
- Subjects
- 3-O-Methylglucose, Animals, Biological Transport, Active, Cytoplasm metabolism, Diuresis, Inulin pharmacokinetics, Kidney Cortex blood supply, Kidney Cortex ultrastructure, Male, Mercuric Chloride pharmacology, Methylglucosides pharmacokinetics, Rabbits, Cycloleucine pharmacokinetics, Kidney Cortex metabolism, p-Aminohippuric Acid pharmacokinetics
- Abstract
The intracellular volume of distribution of the nonmetabolizable sugar derivative 3-O-methylglucose was determined in the renal cortex of diuresing rabbits. This sugar is not well reabsorbed from the lumen, but is readily taken up across the basolateral cell membranes by an apparently flow-limited, nonconcentrative process. The ratio of distribution volumes of nonfiltered 3-O-methylglucose and inulin, therefore, equals the ratio of their mean artery-vein transit times. An intracellular and presumably cytoplasmic volume for 3-O-methylglucose of 0.13 ml/g was thus determined in the cortex of rabbits undergoing mannitol diuresis; similar values were obtained with three other less direct approaches. Availability of a reliable value permitted calculation of the activity gradients against which para-aminohippurate and the neutral amino acid cycloleucine can be accumulated at the basolateral membrane in vivo; both gradients equal about 6:1. This finding underlines the active nature of basolateral amino acid uptake and points to a further characteristic common to the organic anion and the cycloleucine carrier systems.
- Published
- 1993
- Full Text
- View/download PDF
45. Distal motor axonopathy and central nervous system myelin vacuolation caused by cycloleucine, an inhibitor of methionine adenosyltransferase.
- Author
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Lee CC, Surtees R, and Duchen LW
- Subjects
- Animals, Female, Male, Methionine Adenosyltransferase antagonists & inhibitors, Mice, Mice, Inbred BALB C, Motor Neurons ultrastructure, Nervous System Diseases pathology, Axons ultrastructure, Cycloleucine pharmacology, Myelin Sheath ultrastructure, Nervous System Diseases chemically induced, Vacuoles ultrastructure
- Abstract
Cycloleucine (CL), an inhibitor of methionine adenosyltransferase, has previously been used to produce an experimental model of subacute combined degeneration of the spinal cord. A re-investigation of its effects on the morphology of the nervous system and on brain concentrations of methionine and S-adenosylmethionine (SAM) was undertaken. Cycloleucine was administered as a single dose intraperitoneally (2 mg/g body weight) to young mice aged 21 d and adults aged 6 or 10 wks. The 21-day-old mice showed clinical evidence of toxicity within 24 h and thereafter developed progressive muscle weakness and ataxia. Animals did not survive longer than 1 wk. Light and electron microscopic examination of the central and peripheral nervous systems showed that intramyelinic vacuolation developed in the white matter of brain and cord within 12 h. The intramyelinic vacuolation in the white matter of brain and cord became more severe with longer survival, vacuoles coalescing and secondary axonal degeneration becoming evident. There was no myelin vacuolation in peripheral nerves. Axonal lesions occurred in the distal parts of motor nerves within 12-24 h resulting in degeneration of intramuscular nerve fibres and terminals. Later there was evidence of axonal degeneration in tibial and sciatic nerves. Many dorsal root ganglion cells became vacuolated or necrotic and numerous degenerated fibres were noted in the white matter of the spinal cord, particularly in the gracile funiculus. The optic nerves were not affected at any stage. In adult mice the pathology consisted of distal motor axonal degeneration which developed at 1-2 d. Little or no intramyelinic vacuolation in white matter was noted. Brain concentrations of SAM were reduced and levels of methionine became greatly elevated. The morphological effects of CL are considered to be the result of SAM deficiency impairing transmethylation processes known to be important in the formation and stabilization of myelin through the methylation of myelin basic protein. The immature developing central nervous system is much more vulnerable than the fully myelinated adult brain and spinal cord. The distal, predominantly motor axonopathy is a new observation and may be a reflection of the importance of transmethylation processes in the maintenance of axonal terminal membranes and the mechanisms of release of acetylcholine at the neuromuscular junction.
- Published
- 1992
- Full Text
- View/download PDF
46. Uptake of alpha-aminoisobutyric acid and cycloleucine on skeletal muscles in burned rats.
- Author
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Tang YW, Yu YM, and Burke JF
- Subjects
- Animals, Hydrogen-Ion Concentration, Male, Random Allocation, Rats, Rats, Inbred Strains, Aminoisobutyric Acids pharmacokinetics, Burns metabolism, Cycloleucine pharmacokinetics, Muscles metabolism
- Abstract
The uptake of alpha-aminoisobutyric acid (AIB) and aminocyclopentane-carboxylic acid (cycloleucine) was studied in soleus muscles isolated from small rats (body weight 50-60 g) during the first 6 h after a major thermal injury, the so-called 'ebb phase' or 'hypometabolic phase'. Soleus muscles were dissected intact from rats at 0.5, 1, 3 and 6 h after extensive deep burn injury (30 per cent TBSA) and then incubated for 2 h in Krebs-Henseleit bicarbonate buffer (pH 7.4), 5.5 mM glucose, bovine serum albumin and radiolabelled AIB or cycloleucine. The results were expressed as the distribution ratio of AIB or cycloleucine between intracellular and extracellular fluid. The AIB uptake in vitro was found to be significantly increased (30 per cent) in the initial half hour postburn only, and then slowly reduced during the subsequent hours to near the value found in non-burn animals. Muscle cycloleucine uptake in vitro showed no significant change in these studies. In our second study, extensor digitorum longus leg muscle were incubated in Krebs-Henseleit bicarbonate buffer with different pH values (7.2-7.5). No significant difference was found in muscle AIB uptake. In summary, since muscle amino acid uptake remained relatively stable during this period, it is suggested that the alteration of amino acid transport across muscle cells may not be a contributing factor to the alteration of amino acid flux during the early phase of stress.
- Published
- 1992
- Full Text
- View/download PDF
47. Observations on the human pharmacology of cycloleucine.
- Author
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Muggia FM, Loew J, and Horwitz S
- Subjects
- Adult, Cycloleucine therapeutic use, Half-Life, Humans, Male, Neoplasms metabolism, Amino Acids metabolism, Cycloleucine metabolism, Neoplasms drug therapy
- Published
- 1977
48. Experimental cystinuria: the cycloleucine model. II. Amino acid efflux from intestinal and renal tissues.
- Author
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Craan AG and Bergeron M
- Subjects
- Animals, Biological Transport drug effects, Cycloleucine pharmacology, Cysteine metabolism, Cystine metabolism, Female, In Vitro Techniques, Lysine metabolism, Lysine pharmacology, Microvilli metabolism, Models, Biological, Rats, Valine metabolism, Amino Acids metabolism, Cycloleucine metabolism, Cystinuria metabolism, Intestinal Mucosa metabolism
- Abstract
Loading and unloading experiments using intestinal sacs and renal cortex slices were undertaken to ascertain the role of amino acid efflux in cycloleucine-induced amino-aciduria. The presence of cycloleucine, lysine, or valine on the luminal or antiluminal side of the intestine caused an increased leakage of [14C] cycloleucine, [14C] lysine, and [35S] cystine from the tissue. Similar results were obtained when using kidney cortex slices, except for cystine efflux. The latter phenomenon was inhibited by cycloleucine and lysine. Data, also obtained with renal cortex slices, suggest that cystine and cysteine are recognized by different transport sites although one (the oxidized form) may be typically extracellular and the other (the reduced form), intracellular. A comparison of these data with previous works done in our laboratory shows that cycloleucine affects efflux less than influx and further suggests that in rats given cycloleucine, renal transport is impaired only at the brush border level for cystine and at both luminal and antiluminal membranes for dibasic amino acids.
- Published
- 1978
- Full Text
- View/download PDF
49. Phase II study of high-dose intermittent cycloleucine in colorectal malignancies.
- Author
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Dindogru A, Leichman LP, Cummings G, and Baker LH
- Subjects
- Adult, Aged, Cycloleucine therapeutic use, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Amino Acids administration & dosage, Colonic Neoplasms drug therapy, Cycloleucine administration & dosage, Rectal Neoplasms drug therapy
- Published
- 1982
50. Phase II evaluation of cycloleucine in the treatment of patients with disseminated sarcomas.
- Author
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Baker LH, Fraile RJ, Samson MK, and Cummings G
- Subjects
- Adult, Cycloleucine adverse effects, Drug Evaluation, Female, Humans, Male, Neoplasm Metastasis, Sarcoma pathology, Amino Acids therapeutic use, Cycloleucine therapeutic use, Sarcoma drug therapy
- Published
- 1981
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