scholarly journals Cytotoxic effects of streptozotocin and N-nitrosomethylurea on the pancreatic B cells with special regard to the role of nicotinamide–adenine dinucleotide

1974 ◽  
Vol 140 (3) ◽  
pp. 487-494 ◽  
Author(s):  
Rolf Gunnarsson ◽  
Christian Berne ◽  
Claes Hellerström
Keyword(s):  
Insulin Release ◽  
Islet Cells ◽  
Cytotoxic Action ◽  
Glucose Residue ◽  
Cytotoxic Effects ◽  
Pancreatic B Cells ◽  
Effect Of Glucose ◽  
Oxidation Of Glucose ◽  
Nad Depletion

The effects on the pancreatic B cell of streptozotocin and its aglucone derivative N-nitrosomethylurea were investigated in obese–hyperglycaemic mice and their lean littermates. Both streptozotocin and N-nitrosomethylurea were found to be B-cytotoxic although N-nitrosomethylurea produced less islet damage. Both substances decreased the concentrations of NAD+ in the islet cells to about 10% of the control values within 2h after injection. This NAD+ depletion was prevented by injection of nicotinamide 10min after the administration of streptozotocin or N-nitrosomethylurea. In islets taken from animals 10min after injection of streptozotocin or N-nitrosomethylurea there was no stimulatory effect of glucose on the respiration or insulin release and the oxidation of glucose was markedly decreased. Addition of nicotinamide (10mm) to the incubated islets restored glucose stimulation of both the oxygen consumption and insulin release. It is concluded that islet NAD+ depletion is probably important for the B-cytotoxin action of N-nitrosomethylurea and streptozotocin. The glucose residue in the streptozotocin molecule may potentiate the B-cytotoxic action of this drug in mice.

scholarly journals Effects of trifluoperazine and pimozide on stimulus–secretion coupling in pancreatic B-cells Suggestion for a role of calmodulin?

1981 ◽  
Vol 196 (3) ◽  
pp. 771-780 ◽  
Author(s):  
Jean-Claude Henquin
Keyword(s):  
Cyclic Amp ◽  
Insulin Release ◽  
Islet Cells ◽  
Antipsychotic Agents ◽  
Secretory Process ◽  
Dependent Inhibition ◽  
Net Uptake ◽  
Stimulus Secretion Coupling ◽  
Two Phases

The possible involvement of calmodulin in insulin release was evaluated by studying the effects on intact islets of trifluoperazine and pimozide, two antipsychotic agents known to bind strongly to calmodulin in cell-free systems. Trifluoperazine (10–100μm) produced a dose- and time-dependent inhibition of the two phases of glucose-stimulated insulin release. The effect was not reversible by simple washing of the drug, but could be prevented by cytochalasin B or theophylline. Trifluoperazine also inhibited the release induced by glyceraldehyde, oxoisocaproate, tolbutamide or barium, but not that stimulated by 10mm-theophylline or 1mm-3-isobutyl-1-methylxanthine. Pimozide (0.5–10μm) also produced a dose-dependent inhibition of insulin release triggered by glucose, leucine or barium, but did not affect the release induced by methylxanthines. Glucose utilization by islet cells was not modified by trifluoperazine (25μm), which slightly increased cyclic AMP concentration in islets incubated without glucose. The drug did not prevent the increase in cyclic AMP concentration observed after 10min of glucose stimulation, but suppressed it after 60min. Basal or glucose-stimulated Ca2+ influx (5min) was unaffected by 25μm-trifluoperazine, whereas Ca2+net uptake (60min) was inhibited by 20%. Glucose-stimulated Ca2+ uptake was almost unaffected by pimozide. In a Ca2+-free medium, trifluoperazine decreased Ca2+ efflux from the islets and did not prevent the further decrease by glucose; in the presence of Ca2+, the drug again decreased Ca2+ efflux and inhibited the stimulation normally produced by glucose. In the absence of glucose, trifluoperazine lowered the rate of Rb+ efflux from the islets, decreased Rb+ influx (10min), but did not affect Rb+ net uptake (60min). It did not interfere with the ability of glucose to decrease Rb+ efflux rate further and to increase Rb+ net uptake. The results show thus that trifluoperazine does not alter the initial key events of the stimulus–secretion coupling. Its inhibition of insulin release suggests a role of calmodulin at late stages of the secretory process.

Role of CYP2E1 in ketone-stimulated insulin release in pancreatic B-cells

2004 ◽  
Vol 67 (5) ◽  
pp. 875-884 ◽  
Author(s):  
Diane J.Lees Murdock ◽  
Jacqueline Clarke ◽  
Peter R. Flatt ◽  
Yvonne A. Barnett ◽  
Christopher R. Barnett
Keyword(s):  
B Cells ◽  
Insulin Release ◽  
Pancreatic B Cells

Bicarbonate modulation of glucose-9nduced biphasic insulin release by rat islets

1976 ◽  
Vol 231 (3) ◽  
pp. 713-721 ◽  
Author(s):  
JC Henquin ◽  
AE Lambert
Keyword(s):  
Insulin Release ◽  
Islet Cells ◽  
Pancreatic Beta Cell ◽  
Late Phase ◽  
Early Response ◽  
Rat Islets ◽  
Cell Functions ◽  
Biphasic Insulin Release ◽  
Two Phases

The role of HCO3 ions in pancreatic beta-cell functions was evaluated with isolated rat islets. The early phase of insulin release was absent when HCO3 ions were omitted from the medium prior to glucose stimuation, but was augmented if HCO3- withdrawal or reintroduction coincided with glucose increase. The inhibition of the late phase augmented as a function of the duration of HCO3- absence, and its reversibility upon readmission of the anion was delayed. Theophylline and cytochalasin B partially corrected the inhibition of the late phase but failed to restore a rapid response. In the presence of 5 mM NaHCO3, the early response was delayed but the total response was normal. In a HCO3--free medium, glucose oxidation and utilization and glucose transport in islet cells were unaltered. Uptake of calcium was reduced in the absence of HCO3 ions, but normal in 5 mM HCO3-. The results document the importance of HCO3- in insulin release and show that the two phases of glucose-induced secretion are differentially modified by its omission. Some of these findings may be explained by alterations in Ca++ uptake by islet cells. It is suggested that the mechanisms regulating insulin granule extrusion upon stimulation by glucose may be partially different for the two phases of release.

scholarly journals Cytotoxic Action of Serratia marcescens Hemolysin on Human Epithelial Cells

1999 ◽  
Vol 67 (2) ◽  
pp. 817-825 ◽  
Author(s):  
Ralf Hertle ◽  
Martina Hilger ◽  
Sandra Weingardt-Kocher ◽  
Iwan Walev
Keyword(s):  
Epithelial Cells ◽  
Serratia Marcescens ◽  
Lipid Membranes ◽  
Trypan Blue ◽  
Cytotoxic Action ◽  
Cytotoxic Effects ◽  
Atp Level ◽  
Vacuole Formation ◽  
Human Epithelial Cells

ABSTRACT Incubation of human epithelial cells with nanomolar concentrations of chromatographically purified Serratia marcescenshemolysin (ShlA) caused irreversible vacuolation and subsequent lysis of the cells. Vacuolation differed from vacuole formation byHelicobacter pylori VacA. Sublytic doses of ShlA led to a reversible depletion of intracellular ATP. Restoration to the initial ATP level was presumably due to the repair of the toxin damage and was inhibited by cycloheximide. Pores formed in epithelial cells and fibroblasts without disruption of the plasma membrane, and the pores appeared to be considerably smaller than those observed in artificial lipid membranes and in erythrocytes and did not allow the influx of propidium iodide or trypan blue. All cytotoxic effects induced by isolated recombinant ShlA were also obtained with exponentially growingS. marcescens cells. The previously suggested role of the hemolysin in the pathogenicity of S. marcescens is supported by these data.

scholarly journals Effect of glucose on the intracellular pH of pancreatic islet cells

1984 ◽  
Vol 218 (3) ◽  
pp. 887-892 ◽  
Author(s):  
P Lindström ◽  
J Sehlin
Keyword(s):  
Insulin Release ◽  
Intracellular Ph ◽  
Pancreatic Islet ◽  
Basal Insulin ◽  
Islet Cells ◽  
Maximum Effect ◽  
Maximal Effect ◽  
Pancreatic Islet Cells ◽  
Bicarbonate Buffer ◽  
Effect Of Glucose

To characterize the effect of glucose on the intracellular pH (pHi) of pancreatic islet cells, we measured the accumulation of 14C-labelled 5,5-dimethyloxazolidine-2,4-dione ([14C]DMO) in beta-cell-rich islets from ob/ob mice. D-Glucose (20 mM) stimulated insulin release and enhanced the [14C]DMO equilibrium uptake corresponding to an increase of pHi by about 0.15 unit. The glucose effect on DMO uptake was concentration-dependent, with half-maximal effect at about 4 mM-glucose and maximum effect at about 10 mM-glucose. It was inhibited by 20 mM-mannoheptulose and potentiated by 4 mM-L-5-hydroxytryptophan, but not affected by 2 mM-theophylline. Mannoheptulose is an inhibitor and L-5-hydroxytryptophan and theophylline are potentiators of glucose-stimulated insulin release. The glucose-induced increase in pHi appeared rapidly (7 min) and persisted for at least 30 min and it was observed both in bicarbonate/CO2-buffered and in Hepes [4-(2-hydroxyethyl)-1-piperazine-ethanesulphonic acid]-buffered media. Addition of extracellular bicarbonate buffer lowered the pHi, but did not affect basal insulin release, whereas 5 mM-NH4+ increased pHi and induced a 4-fold increase of basal insulin release. We conclude that, in contrast with previous assumptions, glucose increases intracellular pH in the islet cells. This effect may be coupled to the glucose metabolism and associated with triggering of insulin release.

Studies on Synergism between Glucose and Amino Acids with Respect to Insulin Release in vitro

1980 ◽  
Vol 35 (1-2) ◽  
pp. 72-75 ◽  
Author(s):  
Qamar Khalid ◽  
M. Ataur Rahman
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Insulin Release ◽  
Direct Effects ◽  
Isolated Rat Islets ◽  
Effect Of Glucose ◽  
Stimulate Insulin Release

Abstract The mutual enhancement of the effect of insulin release by glucose and amino acids is not clearly understood. Present in vitro studies with isolated rat islets were undertaken to elaborate the role of amino acids on insulin release, particularly their interaction with glucose as well as among each other, which has been reported to lead to synergism in the hum an subjects.In the presence of 8.3 mм glucose, both arginine, as well as, leucine potentiated the effect of glucose which increased progressively with the increasing concentrations of the amino acid. This effect of arginine was not synergistic in nature because arginine did not stimulate insulin release in the absence of glucose.The effect of glucose and leucine was found to be additive and not synergistic.No synergism was exhibited by any of the amino acid pairs tested in the present study. Thus both phenylalanine and lysine did not potentiate the effect of either arginine or leucine. Arginine showed a mild, but significant potentiating effect on leucine-stimulated insulin release.It is suggested that synergism between glucose and amino acids and between certain amino acid pairs reported in m an may not be due to the direct effects of these stimuli on the beta cells, but some other factors in vivo may be involved.

scholarly journals The role of adenosine 3′:5′-cyclic monophosphate in the regulation of insulin release by isolated rat islets of Langerhans

1971 ◽  
Vol 122 (1) ◽  
pp. 115-120 ◽  
Author(s):  
W. Montague ◽  
J. R. Cook
Keyword(s):  
Cyclic Amp ◽  
Insulin Release ◽  
Islets Of Langerhans ◽  
Islet Cells ◽  
Intracellular Concentration ◽  
Release Process ◽  
Cyclic Monophosphate ◽  
Extracellular Glucose ◽  
Rat Islets Of Langerhans ◽  
Effect Of Glucose

1. Concentrations of cyclic AMP (adenosine 3′:5′-cyclic monophosphate) and rates of insulin release were measured in islets of Langerhans isolated from rat pancreas and incubated for various times in the presence of glucose, 3-isobutyl-1-methylxanthine, caffeine, theophylline, adrenaline and diazoxide. 2. Caffeine and theophylline produced small but significant increases in both cyclic AMP and release of insulin when they were incubated in the presence of 10mm-glucose. 3. 3-Isobutyl-1-methylxanthine produced a marked increase in the intracellular concentration of cyclic AMP in the presence of 5mm- and 10mm-glucose. However, insulin release was stimulated only in the presence of 10mm-glucose. 4. In response to rising concentrations of extracellular glucose (5–20mm) there was no detectable increase in the intracellular concentration of cyclic AMP even though there was a marked increase in the rate of insulin release. 5. In response to 10mm-glucose insulin release occurred in two phases and 3-isobutyl-1-methylxanthine potentiated the effect of glucose on both phases. The intracellular concentration of cyclic AMP remained constant with glucose and rose within 10min to its maximum value with 3-isobutyl-1-methylxanthine. 6. Adrenaline and diazoxide inhibited insulin release and lowered the intracellular concentration of cyclic AMP when islets were incubated with glucose or 3-isobutyl-1-methylxanthine. 7. It is suggested that glucose does not stimulate insulin release by increasing the concentration of cyclic AMP in islet cells. However, the concentration of cyclic AMP in islet cells may modulate the effect of glucose on the release process.

Role of tyrosine kinase in insulin release in an insulin secreting cell line (INS-1)

1995 ◽  
Vol 7 (5) ◽  
pp. 505-512 ◽  
Author(s):  
E.J. Verspohl ◽  
B. Tollkühn ◽  
H. Kloss
Keyword(s):  
Tyrosine Kinase ◽  
Cell Line ◽  
Insulin Release ◽  
Secreting Cell

scholarly journals An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Thao Thi Thanh Nguyen ◽  
Masato Shingyoji ◽  
Michiko Hanazono ◽  
Boya Zhong ◽  
Takao Morinaga ◽  
...  
Keyword(s):  
Wild Type ◽  
Inhibitory Effects ◽  
Cytotoxic Effects ◽  
P53 Expression ◽  
Nuclear Factor I ◽  
Infected Cells ◽  
Wild Type P53 ◽  
Mdm2 Inhibitor ◽  
P16 Expression

AbstractA majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

scholarly journals Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yiyi Yao ◽  
Fenglin Li ◽  
Jiansong Huang ◽  
Jie Jin ◽  
Huafeng Wang
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chemotherapy Resistance ◽  
Bone Marrow Microenvironment ◽  
Cytotoxic Effects ◽  
High Relapse Rate ◽  
Underlying Mechanisms ◽  
Acute Myeloid

AbstractDespite the advances in intensive chemotherapy regimens and targeted therapies, overall survival (OS) of acute myeloid leukemia (AML) remains unfavorable due to inevitable chemotherapy resistance and high relapse rate, which mainly caused by the persistence existence of leukemia stem cells (LSCs). Bone marrow microenvironment (BMM), the home of hematopoiesis, has been considered to play a crucial role in both hematopoiesis and leukemogenesis. When interrupted by the AML cells, a malignant BMM formed and thus provided a refuge for LSCs and protecting them from the cytotoxic effects of chemotherapy. In this review, we summarized the alterations in the bidirectional interplay between hematopoietic cells and BMM in the normal/AML hematopoietic environment, and pointed out the key role of these alterations in pathogenesis and chemotherapy resistance of AML. Finally, we focused on the current potential BMM-targeted strategies together with future prospects and challenges. Accordingly, while further research is necessary to elucidate the underlying mechanisms behind LSC–BMM interaction, targeting the interaction is perceived as a potential therapeutic strategy to eradicate LSCs and ultimately improve the outcome of AML.

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