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R J Price - One of the best experts on this subject based on the ideXlab platform.
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Proliferation and Cell Replication in the Rat and Syrian Hamster
2013Co-Authors: B G Lake, J G Evans, M E Cunninghame, R J PriceAbstract:Male Sprague-Dawley rats were fed control diet or diet containing 0.05 % nafenopin (NAF) or 0.025 % WY-14,643 (WY) and male Syrian hamsters were fed control diet or diet containing 0.25% NAF or 0.025 % WY for periods of 1, 15, 40, and 60 weeks. Both NAF and WY produced a sustained increase in liver weight and induction of peroxisomal fatty acid n-oxidation in the rat and Syrian hamster. Replicative DNA synthesis was studied by implanting osmotic pumps containing 13HI thymidine during weeks 0-1, 14-15, 39-40, and 59-60. Cell Replication, determined either as the hepatocyte labelling index or by incorporation of radioactivity into liver whole homogenate DNA, was increased in rats given NAF and WY for 1 week. However, only WY produced a sustained increased in Cell Replication after 15-60 weeks. After 40 weeks, liver nodules and tumors were present in WY-treated rats, and these lesions were observed in all WY-treated and some NAF-treated rats after 60 weeks. In contrast to the rat, no marked effect on replicative DNA synthesis and no liver nodules and tumors were observed in Syrian hamsters given NAF and WY for up to 60 weeks. The rat study demonstrates that liver tumors are produced more rapidly by doses of peroxisome proliferators that produce a sustained stimulation of Cell Replication, whereas the hamster study suggests that species differences may exist in both peroxisome proliferator-induced Cell Replication and liver tumor formation
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Comparison of the hepatic effects of nafenopin and WY-14,643 on peroxisome proliferation and Cell Replication in the rat and Syrian hamster.
Environmental health perspectives, 1993Co-Authors: B G Lake, J G Evans, M E Cunninghame, R J PriceAbstract:Male Sprague-Dawley rats were fed control diet or diet containing 0.05% nafenopin (NAF) or 0.025% WY-14,643 (WY) and male Syrian hamsters were fed control diet or diet containing 0.25% NAF or 0.025% WY for periods of 1, 15, 40, and 60 weeks. Both NAF and WY produced a sustained increase in liver weight and induction of peroxisomal fatty acid beta-oxidation in the rat and Syrian hamster. Replicative DNA synthesis was studied by implanting osmotic pumps containing [3H] thymidine during weeks 0-1, 14-15, 39-40, and 59-60. Cell Replication, determined either as the hepatocyte labelling index or by incorporation of radioactivity into liver whole homogenate DNA, was increased in rats given NAF and WY for 1 week. However, only WY produced a sustained increased in Cell Replication after 15-60 weeks. After 40 weeks, liver nodules and tumors were present in WY-treated rats, and these lesions were observed in all WY-treated and some NAF-treated rats after 60 weeks. In contrast to the rat, no marked effect on replicative DNA synthesis and no liver nodules and tumors were observed in Syrian hamsters given NAF and WY for up to 60 weeks. The rat study demonstrates that liver tumors are produced more rapidly by doses of peroxisome proliferators that produce a sustained stimulation of Cell Replication, whereas the hamster study suggests that species differences may exist in both peroxisome proliferator-induced Cell Replication and liver tumor formation.
Fred Levine - One of the best experts on this subject based on the ideXlab platform.
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Induction of β-Cell Replication by a synthetic HNF4α antagonist.
STEM CELLS, 2013Co-Authors: Seung-hee Lee, Ron Piran, Ehud Keinan, Anthony B. Pinkerton, Fred LevineAbstract:Increasing the number of β Cells is critical to a definitive therapy for diabetes. Previously, we discovered potent synthetic small molecule antagonists of the nuclear receptor transcription factor HNF4α. The natural ligands of HNF4α are thought to be fatty acids. Because obesity, in which there are high circulating levels of free fatty acids, is one of the few conditions leading to β-Cell hyperplasia, we tested the hypothesis that a potent HNF4α antagonist might stimulate β-Cell Replication. A bioavailable HNF4α antagonist was injected into normal mice and rabbits and β-Cell ablated mice and the effect on β-Cell Replication was measured. In normal mice and rabbits, the compound induced β-Cell Replication and repressed the expression of multiple cyclin-dependent kinase inhibitors, including p16 that plays a critical role in suppressing β-Cell Replication. Interestingly, in β-Cell ablated mice, the compound induced α- and δ-Cell, in addition to β-Cell Replication, and β-Cell number was substantially increased. Overall, the data presented here are consistent with a model in which the well-known effects of obesity and high fat diet on β-Cell Replication occur by inhibition of HNF4α. The availability of a potent synthetic HNF4α antagonist raises the possibility that this effect might be a viable route to promote significant increases in β-Cell Replication in diseases with reduced β-Cell mass, including type I and type II diabetes. Stem Cells 2013;31:2396–2407
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Induction of β-Cell Replication by a synthetic HNF4α antagonist.
Stem cells (Dayton Ohio), 2013Co-Authors: Seung-hee Lee, Ron Piran, Ehud Keinan, Anthony B. Pinkerton, Fred LevineAbstract:Increasing the number of β Cells is critical to a definitive therapy for diabetes. Previously, we discovered potent synthetic small molecule antagonists of the nuclear receptor transcription factor HNF4α. The natural ligands of HNF4α are thought to be fatty acids. Because obesity, in which there are high circulating levels of free fatty acids, is one of the few conditions leading to β-Cell hyperplasia, we tested the hypothesis that a potent HNF4α antagonist might stimulate β-Cell Replication. A bioavailable HNF4α antagonist was injected into normal mice and rabbits and β-Cell ablated mice and the effect on β-Cell Replication was measured. In normal mice and rabbits, the compound induced β-Cell Replication and repressed the expression of multiple cyclin-dependent kinase inhibitors, including p16 that plays a critical role in suppressing β-Cell Replication. Interestingly, in β-Cell ablated mice, the compound induced α- and δ-Cell, in addition to β-Cell Replication, and β-Cell number was substantially increased. Overall, the data presented here are consistent with a model in which the well-known effects of obesity and high fat diet on β-Cell Replication occur by inhibition of HNF4α. The availability of a potent synthetic HNF4α antagonist raises the possibility that this effect might be a viable route to promote significant increases in β-Cell Replication in diseases with reduced β-Cell mass, including type I and type II diabetes.
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β-Cell Replication and islet neogenesis following partial pancreatectomy.
Islets, 2011Co-Authors: Seung-hee Lee, Ergeng Hao, Fred LevineAbstract:Partial pancreatectomy is one of the most commonly used models in the study of β-Cell regeneration. The mechanism by which regeneration occurs in this model has been controversial, with some claiming that islet and β-Cell neogenesis is important, while others claim that β-Cell Replication is predominant. Here, we combined a time course analysis with continuous BrdU administration to study β-Cell regeneration following partial pancreatectomy. While exocrine Cells in regenerating areas were highly proliferative and positive for BrdU, islets in regenerating areas were negative for BrdU one week after partial pancreatectomy, suggesting that they were derived from preexisting islets rather than being neogenic. The insulin-positive Cells in ducts that have been reported by others and taken as evidence of β-Cell neogenesis were present in regenerating regions of the pancreas, but were relatively uncommon and were not highly proliferative, suggesting that they could not account for significant islet neogenesis. Consistent with a lack of islet neogenesis, regenerating areas following a second partial pancreatectomy were devoid of islets. β-Cell Replication was detectable at a high frequency two weeks following partial pancreatectomy and was present at a similar frequency in both regenerating and preexisting regions of the pancreas. In summary, our data indicate that islet neogenesis following partial pancreatectomy does not occur.
Peter C. Butler - One of the best experts on this subject based on the ideXlab platform.
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Development of factors to convert frequency to rate for β-Cell Replication and apoptosis quantified by time-lapse video microscopy and immunohistochemistry
American Journal of Physiology-endocrinology and Metabolism, 2008Co-Authors: Yoshifumi Saisho, Peter C. Butler, Erica Manesso, Tatyana Gurlo, Chang-jiang Huang, Gianna Toffolo, Claudio CobelliAbstract:An obstacle to development of methods to quantify β-Cell turnover from pancreas tissue is the lack of conversion factors for the frequency of β-Cell Replication or apoptosis detected by immunohisto...
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β-Cell Replication Is the Primary Mechanism Subserving the Postnatal Expansion of β-Cell Mass in Humans
Diabetes, 2008Co-Authors: Juris J. Meier, Anil Bhushan, Alexandra E. Butler, Yoshifumi Saisho, Travis Monchamp, Ryan Galasso, Robert A. Rizza, Peter C. ButlerAbstract:OBJECTIVE— Little is known about the capacity, mechanisms, or timing of growth in β-Cell mass in humans. We sought to establish if the predominant expansion of β-Cell mass in humans occurs in early childhood and if, as in rodents, this coincides with relatively abundant β-Cell Replication. We also sought to establish if there is a secondary growth in β-Cell mass coincident with the accelerated somatic growth in adolescence. RESEARCH DESIGN AND METHODS— To address these questions, pancreas volume was determined from abdominal computer tomographies in 135 children aged 4 weeks to 20 years, and morphometric analyses were performed in human pancreatic tissue obtained at autopsy from 46 children aged 2 weeks to 21 years. RESULTS— We report that 1 ) β-Cell mass expands by severalfold from birth to adulthood, 2 ) islets grow in size rather than in number during this transition, 3 ) the relative rate of β-Cell growth is highest in infancy and gradually declines thereafter to adulthood with no secondary accelerated growth phase during adolescence, 4 ) β-Cell mass (and presumably growth) is highly variable between individuals, and 5 ) a high rate of β-Cell Replication is coincident with the major postnatal expansion of β-Cell mass. CONCLUSIONS— These data imply that regulation of β-Cell Replication during infancy plays a major role in β-Cell mass in adult humans.
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modestly increased beta Cell apoptosis but no increased beta Cell Replication in recent onset type 1 diabetic patients who died of diabetic ketoacidosis
Diabetologia, 2007Co-Authors: Alexandra E. Butler, Juris J. Meier, Ryan Galasso, Robert A. Rizza, Rita Basu, Peter C. ButlerAbstract:Aims/hypothesis Type 1 diabetes is characterised by a deficit in beta Cell mass thought to be due to immunemediated increased beta Cell apoptosis. Beta Cell turnover has not been examined in the context of new-onset type 1 diabetes with diabetic ketoacidosis. Methods Samples of pancreas were obtained at autopsy from nine patients, aged 12 to 38 years (mean 24.3±3.4 years), who had had type 1 diabetes for less than 3 years before death due to diabetic ketoacidosis. Samples of pancreas obtained at autopsy from nine non-diabetic cases aged 11.5 to 38 years (mean 24.2±3.4 years) were used as control. Fractional beta Cell area (insulin staining), beta Cell Replication (insulin and Ki67 staining) and beta Cell apoptosis (insulin and TUNEL staining) were measured. Results In pancreas obtained at autopsy from recent-onset type 1 diabetes patients who had died of diabetic ketoacidosis, the beta Cell deficit varied from 70 to 99% (mean 90%). The pattern of beta Cell loss was lobular, with almost all beta Cells absent in most pancreatic lobules; islets in lobules not devoid of beta Cells had reduced or a nearnormal complement of beta Cells. Beta Cell apoptosis was increased in recent-onset type 1 diabetes, but to a surprisingly modest degree given the marked hyperglycaemia (30 mmol/l), acidosis and presumably high NEFA. Beta Cell Replication, scattered pancreatic beta Cells and beta Cells in exocrine ducts were not increased in recent-onset type 1 diabetes. Conclusions/interpretation These findings do not support the notion of active beta Cell regeneration by Replication in new-onset type 1 diabetes under conditions of diabetic ketoacidosis. The gluco-lipotoxicity reported in isolated human islets may be less evident in vivo.
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Increased islet beta Cell Replication adjacent to intrapancreatic gastrinomas in humans.
Diabetologia, 2006Co-Authors: Juris J. Meier, Alexandra E. Butler, Ryan Galasso, Robert A. Rizza, Peter C. ButlerAbstract:Aims/hypothesis Type 1 and type 2 diabetes are characterised by a beta Cell deficit. Islet hyperplasia has been described in patients with Zollinger–Ellison syndrome secondary to gastrin-producing tumours (gastrinomas), and gastrin therapy has increased beta Cell mass in rodents and human islets in vitro. In the present studies we addressed the following questions: (1) In pancreas specimens from gastrinoma cases, is the fractional beta Cell area increased? (2) If so, is this restricted to tumour-adjacent islets or also present in tumour-distant islets? (3) Is new beta Cell formation (beta Cell Replication and islet neogenesis) increased and beta Cell apoptosis decreased in pancreas specimens from gastrinoma cases?
Yuval Dor - One of the best experts on this subject based on the ideXlab platform.
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Systemic Regulation of the Age-Related Decline of Pancreatic β-Cell Replication
Diabetes, 2013Co-Authors: Seth J. Salpeter, Benjamin Glaser, Abed Khalaileh, Noa Weinberg-corem, Oren Ziv, Yuval DorAbstract:The frequency of pancreatic β-Cell Replication declines dramatically with age, potentially contributing to the increased risk of type 2 diabetes in old age. Previous studies have shown the involvement of Cell-autonomous factors in this phenomenon, particularly the decline of polycomb genes and accumulation of p16/INK4A. Here, we demonstrate that a systemic factor found in the circulation of young mice is able to increase the proliferation rate of old pancreatic β-Cells. Old mice parabiosed to young mice have increased β-Cell Replication compared with unjoined old mice or old mice parabiosed to old mice. In addition, we demonstrate that old β-Cells transplanted into young recipients have increased Replication rate compared with Cells transplanted into old recipients; conversely, young β-Cells transplanted into old mice decrease their Replication rate compared with young Cells transplanted into young recipients. The expression of p16/INK4A mRNA did not change in heterochronic parabiosis, suggesting the involvement of other pathways. We conclude that systemic factors contribute to the replicative decline of old pancreatic β-Cells.
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Glucose and aging control the quiescence period that follows pancreatic beta Cell Replication
Development, 2010Co-Authors: Seth J. Salpeter, Allon M. Klein, Danwei Huangfu, Joseph Grimsby, Yuval DorAbstract:Pancreatic beta Cell proliferation has emerged as the principal mechanism for homeostatic maintenance of beta Cell mass during adult life. This underscores the importance of understanding the mechanisms of beta Cell Replication and suggests novel approaches for regenerative therapy to treat diabetes. Here we use an in vivo pulse-chase labeling assay to investigate the Replication dynamics of adult mouse beta Cells. We find that replicated beta Cells are able to re-enter the Cell division cycle shortly after mitosis and regain their normal proliferative potential after a short quiescence period of several days. This quiescence period is lengthened with advanced age, but shortened during injury-driven beta Cell regeneration and following treatment with a pharmacological activator of glucokinase, providing strong evidence that metabolic demand is a key determinant of Cell cycle re-entry. Lastly, we show that cyclin D2, a crucial factor in beta Cell Replication, is downregulated during Cell division, and is slowly upregulated post-mitosis by a glucose-sensitive mechanism. These results demonstrate that beta Cells quickly regain their capacity to re-enter the Cell cycle post-mitosis and implicate glucose control of cyclin D2 expression in the regulation of this process.
B G Lake - One of the best experts on this subject based on the ideXlab platform.
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Proliferation and Cell Replication in the Rat and Syrian Hamster
2013Co-Authors: B G Lake, J G Evans, M E Cunninghame, R J PriceAbstract:Male Sprague-Dawley rats were fed control diet or diet containing 0.05 % nafenopin (NAF) or 0.025 % WY-14,643 (WY) and male Syrian hamsters were fed control diet or diet containing 0.25% NAF or 0.025 % WY for periods of 1, 15, 40, and 60 weeks. Both NAF and WY produced a sustained increase in liver weight and induction of peroxisomal fatty acid n-oxidation in the rat and Syrian hamster. Replicative DNA synthesis was studied by implanting osmotic pumps containing 13HI thymidine during weeks 0-1, 14-15, 39-40, and 59-60. Cell Replication, determined either as the hepatocyte labelling index or by incorporation of radioactivity into liver whole homogenate DNA, was increased in rats given NAF and WY for 1 week. However, only WY produced a sustained increased in Cell Replication after 15-60 weeks. After 40 weeks, liver nodules and tumors were present in WY-treated rats, and these lesions were observed in all WY-treated and some NAF-treated rats after 60 weeks. In contrast to the rat, no marked effect on replicative DNA synthesis and no liver nodules and tumors were observed in Syrian hamsters given NAF and WY for up to 60 weeks. The rat study demonstrates that liver tumors are produced more rapidly by doses of peroxisome proliferators that produce a sustained stimulation of Cell Replication, whereas the hamster study suggests that species differences may exist in both peroxisome proliferator-induced Cell Replication and liver tumor formation
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Comparison of the hepatic effects of nafenopin and WY-14,643 on peroxisome proliferation and Cell Replication in the rat and Syrian hamster.
Environmental health perspectives, 1993Co-Authors: B G Lake, J G Evans, M E Cunninghame, R J PriceAbstract:Male Sprague-Dawley rats were fed control diet or diet containing 0.05% nafenopin (NAF) or 0.025% WY-14,643 (WY) and male Syrian hamsters were fed control diet or diet containing 0.25% NAF or 0.025% WY for periods of 1, 15, 40, and 60 weeks. Both NAF and WY produced a sustained increase in liver weight and induction of peroxisomal fatty acid beta-oxidation in the rat and Syrian hamster. Replicative DNA synthesis was studied by implanting osmotic pumps containing [3H] thymidine during weeks 0-1, 14-15, 39-40, and 59-60. Cell Replication, determined either as the hepatocyte labelling index or by incorporation of radioactivity into liver whole homogenate DNA, was increased in rats given NAF and WY for 1 week. However, only WY produced a sustained increased in Cell Replication after 15-60 weeks. After 40 weeks, liver nodules and tumors were present in WY-treated rats, and these lesions were observed in all WY-treated and some NAF-treated rats after 60 weeks. In contrast to the rat, no marked effect on replicative DNA synthesis and no liver nodules and tumors were observed in Syrian hamsters given NAF and WY for up to 60 weeks. The rat study demonstrates that liver tumors are produced more rapidly by doses of peroxisome proliferators that produce a sustained stimulation of Cell Replication, whereas the hamster study suggests that species differences may exist in both peroxisome proliferator-induced Cell Replication and liver tumor formation.