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Subramanyam Muthangi - One of the best experts on this subject based on the ideXlab platform.
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survival of silk worm bombyx mori in Azaserine induced oxidative stress
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2020Co-Authors: Venkatesh Mandyam D, Subramanyam MuthangiAbstract:Abstract Cells under stress generate reactive oxygen species (ROS) in excess, which causes mitochondrial dysfunction and stimulates the apoptotic cascade. However, mild stress or pre-conditioning lead to the evasion of apoptosis by activating mitogenic signaling, including the signaling of inhibitors of apoptosis proteins (IAPs), or by inactivating certain apoptotic molecules. The silkworm (Bombyx mori) is an important economic insect which serves as a model organism in biological research. Bombyx mori apoptotic protease inducing factor (BmApaf1), a death-related ced-3/Nedd2-like protein (BmDredd), and BmSurvivin-2 (BmSvv2) are known to play significant roles in metamorphosis. Azaserine is an analogue of glutamine and irreversibly inhibits glutamine-utilizing enzymes and cysteine-glutamate transporter genes EAAT2. In the present study, we experimentally demonstrated stress induced by Azaserine along with the capacity of antioxidants to modulate apoptotic/anti-apoptotic gene expression in determining the fate of the larvae. We observed higher larval survival with higher Azaserine dosages and attributed this to the quantum of ROS generated and AOEs response, which favoured the BmSvv2 expression. Meanwhile higher levels of ROS with concomitant changes in AOEs were found to be responsible for BmApaf1 and BmDredd expression, which reflected a higher mortality rate.
Venkatesh Mandyam D - One of the best experts on this subject based on the ideXlab platform.
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survival of silk worm bombyx mori in Azaserine induced oxidative stress
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2020Co-Authors: Venkatesh Mandyam D, Subramanyam MuthangiAbstract:Abstract Cells under stress generate reactive oxygen species (ROS) in excess, which causes mitochondrial dysfunction and stimulates the apoptotic cascade. However, mild stress or pre-conditioning lead to the evasion of apoptosis by activating mitogenic signaling, including the signaling of inhibitors of apoptosis proteins (IAPs), or by inactivating certain apoptotic molecules. The silkworm (Bombyx mori) is an important economic insect which serves as a model organism in biological research. Bombyx mori apoptotic protease inducing factor (BmApaf1), a death-related ced-3/Nedd2-like protein (BmDredd), and BmSurvivin-2 (BmSvv2) are known to play significant roles in metamorphosis. Azaserine is an analogue of glutamine and irreversibly inhibits glutamine-utilizing enzymes and cysteine-glutamate transporter genes EAAT2. In the present study, we experimentally demonstrated stress induced by Azaserine along with the capacity of antioxidants to modulate apoptotic/anti-apoptotic gene expression in determining the fate of the larvae. We observed higher larval survival with higher Azaserine dosages and attributed this to the quantum of ROS generated and AOEs response, which favoured the BmSvv2 expression. Meanwhile higher levels of ROS with concomitant changes in AOEs were found to be responsible for BmApaf1 and BmDredd expression, which reflected a higher mortality rate.
Hidehiko Kumagai - One of the best experts on this subject based on the ideXlab platform.
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crystal structures of escherichia coli gamma glutamyltranspeptidase in complex with Azaserine and acivicin novel mechanistic implication for inhibition by glutamine antagonists
Journal of Molecular Biology, 2008Co-Authors: Kei Wada, Hideyuki Suzuki, Hidehiko Kumagai, Jun Hiratake, Machiko Irie, Toshihiro Okada, Chiaki Yamada, Keiichi FukuyamaAbstract:Abstract γ-Glutamyltranspeptidase (GGT) catalyzes the cleavage of such γ-glutamyl compounds as glutathione, and the transfer of their γ-glutamyl group to water or to other amino acids and peptides. GGT is involved in a number of biological phenomena such as drug resistance and metastasis of cancer cells by detoxification of xenobiotics. Azaserine and acivicin are classical and irreversible inhibitors of GGT, but their binding sites and the inhibition mechanisms remain to be defined. We have determined the crystal structures of GGT from Escherichia coli in complex with Azaserine and acivicin at 1.65 A resolution. Both inhibitors are bound to GGT at its substrate-binding pocket in a manner similar to that observed previously with the γ-glutamyl-enzyme intermediate. They form a covalent bond with the O γ atom of Thr391, the catalytic residue of GGT. Their α-carboxy and α-amino groups are recognized by extensive hydrogen bonding and charge interactions with the residues that are conserved among GGT orthologs. The two amido nitrogen atoms of Gly483 and Gly484, which form the oxyanion hole, interact with the inhibitors directly or via a water molecule. Notably, in the Azaserine complex the carbon atom that forms a covalent bond with Thr391 is sp 3 -hybridized, suggesting that the carbonyl of Azaserine is attacked by Thr391 to form a tetrahedral intermediate, which is stabilized by the oxyanion hole. Furthermore, when acivicin is bound to GGT, a migration of the single and double bonds occurs in its dihydroisoxazole ring. The structural characteristics presented here imply that the unprecedented binding modes of Azaserine and acivicin are conserved in all GGTs from bacteria to mammals and give a new insight into the inhibition mechanism of glutamine amidotransferases by these glutamine antagonists.
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the liv i ls system as a determinant of Azaserine sensitivity of escherichia coli k 12
Fems Microbiology Letters, 2004Co-Authors: Takashi Koyanagi, Takane Katayama, Hideyuki Suzuki, Hidehiko KumagaiAbstract:The growth of Escherichia coli is inhibited by an antibiotic compound, Azaserine (O-diazoacetyl-l-serine). Previous studies revealed the biochemical properties of Azaserine, which involves inhibition of various enzymatic reactions as well as introduction of DNA breakage. However, genetically, nothing has been elucidated except that all the Azaserine-resistant strains isolated so far carry lesions in the aroP gene as a primary determinant. Here, we demonstrate that, in addition to AroP, the LIV-I/LS system, an ATP-binding cassette type transporter, is involved in Azaserine sensitivity of E. coli, by genetic analysis and transport studies, in which Ki value for Azaserine was determined to be ∼10−3 M.
Daniel S. Longnecker - One of the best experts on this subject based on the ideXlab platform.
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temporal expression of the gastrin cck b receptor during Azaserine induced pancreatic carcinogenesis
Pancreas, 1993Co-Authors: Stephen P Povoski, Daniel S. Longnecker, Weigong Zhou, Richard H BellAbstract:: Cholecystokinin (CCK-A) and gastrin (CCK-B) receptors have been demonstrated in the Azaserine-induced rat pancreatic carcinoma DSL-6. In order to determine at what stage in Azaserine-induced pancreatic carcinogenesis gastrin (CCK-B) receptors are first expressed, we examined the binding of [125I]gastrin-I to normal rat pancreas, Azaserine-induced premalignant pancreatic nodules, grossly normal internodular pancreas, and DSL-6 carcinoma. We observed that specific gastrin binding was absent in normal pancreas, premalignant nodules, and internodular pancreas, and also reconfirmed our previous report of marked overexpression of gastrin (CCK-B) receptors in the DSL-6 carcinoma. Specific cholecystokinin (CCK) binding was present in all pancreatic tissue types tested. Therefore, we conclude that the presence of gastrin (CCK-B) receptors in the Azaserine-induced pancreatic carcinoma DSL-6, in contrast to their absence in premalignant nodules, suggests that the expression of the gastrin (CCK-B) receptor may be important in the transformation from premalignant nodules to pancreatic cancer.
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overexpression of cholecystokinin receptors in Azaserine induced neoplasms of the rat pancreas
Cancer Research, 1992Co-Authors: Richard H Bell, Elna T. Kuhlmann, Robert T Jensen, Daniel S. LongneckerAbstract:Abstract Cholecystokinin (CCK) is a growth factor for normal pancreas. Numerous studies also suggest that CCK promotes pancreatic carcinogenesis in the rat. Our previous studies suggested that growth of preneoplastic pancreatic foci was stimulated by CCK more than that of normal pancreas. We hypothesized that such differential growth might be due to increased numbers of CCK receptors in neoplastic tissue. Azaserine-induced pancreatic carcinoma (DSL6) had an increased high-affinity CCK receptor binding capacity of 122 ± 23 (SD) fmol/mg protein compared to 12 ± 2 fmol/mg protein in normal pancreas (P Azaserine-induced premalignant nodules were compared to remaining internodular pancreas. Nodules demonstrated a mean high-affinity CCK receptor binding capacity of 38 ± 9 fmol/mg protein compared to 6 ± 3 fmol/mg protein in internodular pancreas (P Overexpression of high-affinity CCK-8 receptor in premalignant and malignant Azaserine-induced tumors may result in a growth advantage relative to normal pancreas.
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cyclosporine inhibition of Azaserine induced atypical acinar cell foci in rat pancreas
Pancreas, 1990Co-Authors: Hisashi Shinozuka, Bill D. Roebuck, Daniel S. LongneckerAbstract:: The effects of cyclosporine (CsA), an immunosuppressive agent, on Azaserine-induced pancreatic carcinogenesis in rats were investigated using the short-term assays of the quantitation of atypical acinar cell foci. Male Lewis rats at 14 days of age were given a single intraperitoneal injection of Azaserine (30 mg/kg). At 25 days of age, the treated rats were weaned and divided into two groups fed either basal diet or the same diet containing 0.011% CsA. Saline-injected rats were also fed the CsA diet. Rats were killed 4 months after Azaserine injection and acidophilic and basophilic foci in the pancreas were quantified. The pancreas of the rats given saline injection and maintained on the CsA diet showed no significant histological alterations. The dietary CsA after the injection of Azaserine markedly reduced the number of both acidophilic and basophilic foci. It is concluded that addition of CsA to the diet inhibits the growth of initiated cells to form foci in the pancreas of Azaserine-treated rats. The experimental model is useful in analyzing the modifying role of this immunosuppressant in the induction and growth of epithelial cell tumors.
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expression of c myc c raf 1 and c ki ras in Azaserine induced pancreatic carcinomas and growing pancreas in rats
Molecular Carcinogenesis, 1990Co-Authors: Jeffrey A Silverman, Elna T. Kuhlmann, Joanne Zurlo, James D Yager, Daniel S. LongneckerAbstract:: We examined the pattern of expression of several proto-oncogenes during nonneoplastic growth and in acinar cell neoplasms in the rat pancreas. The levels of c-myc, c-raf-1, and c-Ki-ras mRNAs were increased in regenerating pancreata following surgical partial pancreatectomy and following administration of camostat. We also investigated proto-oncogene expression associated with the progression of pancreatic cancers in Azaserine-treated rats. Injection of a single dose (30 mg/kg) of Azaserine (O-diazoacetyl-L-serine) to 14-d-old rats leads to a variety of neoplastic lesions in the rat pancreas. Total RNA was isolated from lesions in various stages of tumor progression, including adenomas, carcinomas in situ, and invasive carcinomas. We observed increased expression of c-myc, c-raf-1, and c-Ki-ras in Azaserine-induced adenomas and carcinomas. Actin expression was also increased in these tissues, whereas amylase expression was variable. However, when compared to the normal growing pancreas, the level of proto-oncogene expression in the adenomas and carcinomas was disproportionate to the degree of cellular division in those tissues. Thus, the alterations induced by Azaserine apparently caused a deregulated increase in expression of cellular oncogenes associated with growth regulation.
Richard H Bell - One of the best experts on this subject based on the ideXlab platform.
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autoradiographic localization of cholecystokinin cck receptor expression during the development of Azaserine induced rat pancreatic carcinoma
Pancreas, 1996Co-Authors: Betty J Tsuei, Stephen P Povoski, Weigong Zhou, Richard H BellAbstract:The peptide hormone cholecystokinin (CCK) has been shown to stimulate the growth of Azaserine-induced preneoplastic nodules in the rat pancreas. Previously, our laboratory demonstrated by classical binding studies that CCK receptors are overexpressed in Azaserine-induced rat pancreatic neoplasms. In the present study, we utilized autoradiography to determine the temporal course of this increased receptor binding. Male Lewis rats were given Azaserine or saline injections and sacrificed at 2, 4, 8, 12, and 18 months of age. Pancreatic tissue was harvested and autoradiography using 125 I-labeled- CCK-8 was performed. Densitometry measurements of Azaserine-induced pancreatic nodules, internodular pancreas, and normal pancreatic tissue (from saline-treated controls) of each age group were taken with an image analyzer. There was no statistically significant difference in CCK binding to internodular pancreas and normal pancreas at any age. At 2 months of age, there was no significant increase in CCK binding to Azaserine-induced pancreatic nodules. However, at 4, 8, 12, and 18 months of age there was significantly greater CCK binding to Azaserine-induced pancreatic nodules than to both internodular pancreas and normal pancreas (p < 0.001 for all groups). At 18 months of age, one Azaserine-treated animal developed a pancreatic acinar cell carcinoma, which likewise exhibited significantly greater CCK binding than internodular pancreas or normal pancreas (p < 0.001 for both). These findings demonstrate increased CCK binding in Azaserine-induced preneoplastic pancreatic nodules and pancreatic acinar cell carcinoma, compatible with our previous demonstration of receptor overexpression in these tissues. Increased CCK binding first becomes apparent by 4 months following exposure to Azaserine. These results suggest that overexpression of CCK receptors, located specifically on preneoplastic and neoplastic pancreatic lesions, results in increased CCK binding and is involved in the mediation of CCK-stimulated growth during Azaserine-induced pancreatic carcinogenesis.
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gastrin receptor expression during Azaserine induced rat pancreatic carcinogenesis
Journal of Surgical Research, 1996Co-Authors: Betty J Tsuei, Stephen P Povoski, Weigong Zhou, Richard H BellAbstract:Abstract The hormone gastrin is thought to stimulate the growth of certain pancreatic carcinoma cell lines. We have previously detected the presence of the gastrin receptor in rat pancreatic carcinoma cell lines but not in normal rat pancreas. We had not, however, previously demonstrated that gastrin receptor is expressed in pancreatic carcinomas developing in the ratin vivo.Therefore, in the present study, we examined rat pancreatic tissue at various stages in Azaserine-induced pancreatic carcinogenesis for gastrin binding and for the presence of gastrin receptor mRNA to determine the temporal expression pattern of the gastrin receptor during thein vivodevelopment of pancreatic cancer. Autoradiography of pancreatic tissue using125I-gastrin-17-I from all Azaserine-treated and control animals at 2, 4, 8, and 12 months of age demonstrated no specific gastrin binding. At 18 months of age, normal pancreas, Azaserine-induced premalignant pancreatic nodules, and internodular pancreas demonstrated no specific gastrin binding. One of three Azaserine-treated animals developed an area of pancreatic acinar cell carcinoma at 18 months of age which exhibited significant specific gastrin binding of 141.8 ± 32.8 fmole/gm of tissue. Southern blot analysis of pancreatic RNA isolated from animals at 12 months of age revealed no gastrin receptor mRNA; however, by 18 months of age, gastrin receptor mRNA was present in all Azaserine-treated animals but absent in control animals. In summary, specific gastrin binding is present inin vivoAzaserine-induced pancreatic acinar cell carcinoma but absent in normal pancreas and Azaserine-induced premalignant pancreatic nodules. Gastrin receptor mRNA is first expressed in Azaserine-treated rat pancreas at some point between 12 and 18 months of age. These results demonstrate that expression of gastrin receptor is altered in Azaserine-treated rat pancreas and may play a role in the development of pancreatic cancer.
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temporal expression of the gastrin cck b receptor during Azaserine induced pancreatic carcinogenesis
Pancreas, 1993Co-Authors: Stephen P Povoski, Daniel S. Longnecker, Weigong Zhou, Richard H BellAbstract:: Cholecystokinin (CCK-A) and gastrin (CCK-B) receptors have been demonstrated in the Azaserine-induced rat pancreatic carcinoma DSL-6. In order to determine at what stage in Azaserine-induced pancreatic carcinogenesis gastrin (CCK-B) receptors are first expressed, we examined the binding of [125I]gastrin-I to normal rat pancreas, Azaserine-induced premalignant pancreatic nodules, grossly normal internodular pancreas, and DSL-6 carcinoma. We observed that specific gastrin binding was absent in normal pancreas, premalignant nodules, and internodular pancreas, and also reconfirmed our previous report of marked overexpression of gastrin (CCK-B) receptors in the DSL-6 carcinoma. Specific cholecystokinin (CCK) binding was present in all pancreatic tissue types tested. Therefore, we conclude that the presence of gastrin (CCK-B) receptors in the Azaserine-induced pancreatic carcinoma DSL-6, in contrast to their absence in premalignant nodules, suggests that the expression of the gastrin (CCK-B) receptor may be important in the transformation from premalignant nodules to pancreatic cancer.
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overexpression of cholecystokinin receptors in Azaserine induced neoplasms of the rat pancreas
Cancer Research, 1992Co-Authors: Richard H Bell, Elna T. Kuhlmann, Robert T Jensen, Daniel S. LongneckerAbstract:Abstract Cholecystokinin (CCK) is a growth factor for normal pancreas. Numerous studies also suggest that CCK promotes pancreatic carcinogenesis in the rat. Our previous studies suggested that growth of preneoplastic pancreatic foci was stimulated by CCK more than that of normal pancreas. We hypothesized that such differential growth might be due to increased numbers of CCK receptors in neoplastic tissue. Azaserine-induced pancreatic carcinoma (DSL6) had an increased high-affinity CCK receptor binding capacity of 122 ± 23 (SD) fmol/mg protein compared to 12 ± 2 fmol/mg protein in normal pancreas (P Azaserine-induced premalignant nodules were compared to remaining internodular pancreas. Nodules demonstrated a mean high-affinity CCK receptor binding capacity of 38 ± 9 fmol/mg protein compared to 6 ± 3 fmol/mg protein in internodular pancreas (P Overexpression of high-affinity CCK-8 receptor in premalignant and malignant Azaserine-induced tumors may result in a growth advantage relative to normal pancreas.
