scholarly journals Rhein Induces a Necrosis-Apoptosis Switch in Pancreatic Acinar Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Xianlin Zhao ◽  
Juan Li ◽  
Shifeng Zhu ◽  
Yiling Liu ◽  
Jianlei Zhao ◽  
...  
Keyword(s):  
Annexin V ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Necrotic Cell ◽  
Ar42j Cells ◽  
Associated Proteins ◽  
Apoptosis And Necrosis ◽  
Dose Dependent

Objectives. The Chinese herbal medicine Da-Cheng-Qi decoction can regulate a necrosis-apoptosis switch in injured pancreatic acinar cells. This study investigated the effects of rhein, a component of this medicine, on a necrosis-apoptosis switch in pancreatic rat AR42J cells.Methods. Cerulein-treated AR42J cells were used. After pretreatment with 479, 119.8, or 29.9 μg/L rhein, cells were cocultured with rhein and cerulein (10−8 M) for 4, 8, or 16 h. Apoptosis and necrosis were examined using annexin V and propidium iodide costaining. Mitochondria-dependent apoptosis-associated proteins were examined using enzyme-linked immunosorbent assays and western blotting.Results. Few cells died in untreated samples. The number was significantly higher in 16-h-cerulein-treated samples and treatment with 479 μg/L rhein most effectively increased the apoptotic-to-necrotic cell ratio (P<0.05). In cerulein-treated cells, rhein increased the concentrations of p53, cytochrome C, and caspase-3, and increased the Bax/Bcl-2 ratio in a time- and dose-dependent manner, with the maximum effect in cells treated with 479 μg/L rhein for 16 h (P<0.05).Conclusions. Rhein induces the necrosis-apoptosis switch in injured pancreatic acinar cells in a time- and dose-dependent manner. Mitochondria-dependent apoptosis signaling pathways might play an important role in this effect.

Prostaglandin E2 modulates TNF-α-induced MCP-1 synthesis in pancreatic acinar cells in a PKA-dependent manner

2007 ◽  
Vol 293 (6) ◽  
pp. G1196-G1204 ◽  
Author(s):  
Li-Kang Sun ◽  
Theresia Reding ◽  
Martha Bain ◽  
Mathias Heikenwalder ◽  
Daniel Bimmler ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Synergistic Effect ◽  
Tissue Injury ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Ar42j Cells ◽  
Tnf Α ◽  
Cox 2

Cyclooxygenase (COX)-2 is increased in human chronic pancreatitis. We recently demonstrated in a model of chronic pancreatitis (WBN/Kob rat) that inhibition of COX-2 activity reduces and delays pancreatic inflammation and fibrosis. Monocyte chemoattractant protein (MCP)-1 mRNA and PGE2 were significantly reduced, correlating with a decreased infiltration of macrophages. MCP-1 plays an important role in the recruitment of macrophages to the site of tissue injury. The aim of our study is to identify mechanisms by which macrophages and acinar cells maintain an inflammatory reaction. The expression profile of E prostanoid receptors EP1-4 and MCP-1 was analyzed by RT-PCR from pancreatic specimens and AR42J cells. MCP-1 secretion was detected by ELISA from rat pancreatic lobuli. We determined EP1-4 mRNA levels in WBN/Kob rats with chronic pancreatic inflammation. Individual isoforms were highly increased in rat pancreas, concurrent with MCP-1 mRNA expression. In supernatants of pancreatic lobuli and AR42J cells, MCP-1 was detectable by ELISA. In the presence of TNF-α, MCP-1 was upregulated. Coincubation with PGE2 enhanced the TNF-α-induced MCP-1 synthesis significantly. Similarly, TNF-α mRNA was synergistically upregulated by TNF-α and PGE2. Furthermore, the synergistic effect of TNF-α and PGE2 was abolished by inhibition of PKA but not of PKC. We conclude that EP receptors are upregulated during chronic pancreatic inflammation. PGE2 modulates the TNF-α-induced MCP-1 synthesis and secretion from acinar cells. This synergistic effect is controlled by PKA. This mechanism might explain the COX-2-dependent propagation of pancreatic inflammation.

Activin A: negative regulator of amylase secretion and cell proliferation in rat pancreatic acinar AR42J cells

1994 ◽  
Vol 267 (2) ◽  
pp. G220-G226
Author(s):  
H. Yasuda ◽  
S. Tanaka ◽  
H. Ohnishi ◽  
H. Mashima ◽  
N. Ogushi ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Pancreatic Islet ◽  
Activin A ◽  
Negative Regulator ◽  
Pancreatic Acinar Cells ◽  
Amylase Secretion ◽  
Dependent Manner ◽  
Amylase Release ◽  
Ar42j Cells ◽  
Dose Dependent

Activin A, a member of the transforming growth factor-beta supergene family, exists in secretory granules of non-B-cells of rat pancreatic islet (H. Yasuda, K. Inoue, H. Shibata, T. Takeuchi, Y. Eto, Y. Hasegawa, N. Sekine, Y. Totsuka, T. Mine, E. Ogata, and I. Kojima. Endocrinology 133: 624-630, 1993). Because functions of exocrine pancreas are influenced by hormones in pancreatic islet, it is possible that activin A affects the function of pancreatic acinar cells. To examine this possibility, we studied the effects of activin A on amylase secretion and DNA synthesis in AR42J cells. In these cells, dexamethasone (Dx) induces increases in secretory organelles and secretion of amylase (C. D. Logsdon, J. Moessner, J. A. Williams, and I. D. Goldfine. J. Cell Biol. 100: 1200-1208 1985). Activin A did not change the rate of amylase release by itself nor affect the cholecystokinin-stimulated amylase release from Dx-treated differentiated AR42J cells. However, when activin A was added together with Dx, activin A inhibited Dx-induced increase in amylase content in a dose-dependent manner. In the presence of 1 nM activin A, the effect of Dx was abolished. In the absence of Dx, amylase content of the cells was also reduced by activin A in a dose-dependent manner. The maximum inhibitory effect was obtained by 10 nM activin A, and at this concentration amylase content became undetectable. In addition, activin A potently inhibited DNA synthesis as assessed by [3H]thymidine incorporation.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Calcium Wave Propagation in Pancreatic Acinar Cells

2000 ◽  
Vol 116 (4) ◽  
pp. 547-560 ◽  
Author(s):  
Stephen V. Straub ◽  
David R. Giovannucci ◽  
David I. Yule
Keyword(s):  
Acinar Cells ◽  
Cytosolic Calcium ◽  
Pancreatic Acinar Cells ◽  
Dependent Manner ◽  
Mitochondrial Import ◽  
Simple Diffusion ◽  
Agonist Stimulation ◽  
Trigger Zone ◽  
Rapid Activation ◽  
Dose Dependent

In pancreatic acinar cells, inositol 1,4,5-trisphosphate (InsP3)–dependent cytosolic calcium ([Ca2+]i) increases resulting from agonist stimulation are initiated in an apical “trigger zone,” where the vast majority of InsP3 receptors (InsP3R) are localized. At threshold stimulation, [Ca2+]i signals are confined to this region, whereas at concentrations of agonists that optimally evoke secretion, a global Ca2+ wave results. Simple diffusion of Ca2+ from the trigger zone is unlikely to account for a global [Ca2+]i elevation. Furthermore, mitochondrial import has been reported to limit Ca2+ diffusion from the trigger zone. As such, there is no consensus as to how local [Ca2+]i signals become global responses. This study therefore investigated the mechanism responsible for these events. Agonist-evoked [Ca2+]i oscillations were converted to sustained [Ca2+]i increases after inhibition of mitochondrial Ca2+ import. These [Ca2+]i increases were dependent on Ca2+ release from the endoplasmic reticulum and were blocked by 100 μM ryanodine. Similarly, “uncaging” of physiological [Ca2+]i levels in whole-cell patch-clamped cells resulted in rapid activation of a Ca2+-activated current, the recovery of which was prolonged by inhibition of mitochondrial import. This effect was also abolished by ryanodine receptor (RyR) blockade. Photolysis of d-myo InsP3 P4(5)-1-(2-nitrophenyl)-ethyl ester (caged InsP3) produced either apically localized or global [Ca2+]i increases in a dose-dependent manner, as visualized by digital imaging. Mitochondrial inhibition permitted apically localized increases to propagate throughout the cell as a wave, but this propagation was inhibited by ryanodine and was not seen for minimal control responses resembling [Ca2+]i puffs. Global [Ca2+]i rises initiated by InsP3 were also reduced by ryanodine, limiting the increase to a region slightly larger than the trigger zone. These data suggest that, while Ca2+ release is initially triggered through InsP3R, release by RyRs is the dominant mechanism for propagating global waves. In addition, mitochondrial Ca2+ import controls the spread of Ca2+ throughout acinar cells by modulating RyR activation.

Both low- and high-affinity CCK receptor states mediate trophic effects on rat pancreatic acinar cells

1993 ◽  
Vol 265 (6) ◽  
pp. G1177-G1181 ◽  
Author(s):  
H. Hoshi ◽  
C. D. Logsdon
Keyword(s):  
Dna Synthesis ◽  
Molecular Mechanisms ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Amylase Release ◽  
High Affinity ◽  
Affinity Receptor ◽  
Dose Dependent

Cholecystokinin (CCK) stimulates the growth of pancreatic acinar cells. However, the molecular mechanisms involved in this trophic action are unknown. CCK binds to both high- and low-affinity receptor states, and these two states appear to activate separate sets of intracellular messengers and have opposite effects on amylase release. JMV-180 is a CCK analogue that interacts in the rat with the high-affinity state as an agonist and the low-affinity state as an antagonist. In the current study, CCK octapeptide (CCK-8) and JMV-180 were tested for their ability to stimulate the growth of rat pancreatic acinar cells in primary culture. CCK-8 stimulated [3H]thymidine incorporation into DNA in a dose-dependent manner. Effects were observed with 0.3 nM, and maximal increases were seen at 3 nM CCK-8 (442 +/- 53% of control, n = 5, P < 0.01). JMV-180 also stimulated DNA synthesis. Effects were noted with 10 nM, and a maximal increase of 267 +/- 82% (n = 4, P < 0.01) of control was stimulated by 100 nM JMV-180. These data with JMV-180 indicate that the high-affinity receptor state for CCK is capable of stimulating DNA synthesis. However, within the same experiment the effects of CCK were always significantly greater than those of JMV-180. To test whether CCK has an additional effect through interactions with the low-affinity state, the effects of a combination of JMV-180 with a maximal dose of CCK-8 were examined. JMV-180 inhibited the maximal effect of CCK-8 in a dose-dependent manner with a maximal inhibition occurring with 1 microM JMV-180. The effects of the combination of 3 nM CCK-8 and 1 microM JMV-180 were no greater than those of JMV-180 alone. Taken together these data indicate that CCK-mediated increases in DNA synthesis in rat pancreatic acinar cells in vitro occur by interactions with both high- and low-affinity receptor states.

scholarly journals Astaxanthin Inhibits Interleukin-6 Expression in Cerulein/Resistin-Stimulated Pancreatic Acinar Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Min Seung Kwak ◽  
Joo Weon Lim ◽  
Hyeyoung Kim
Keyword(s):  
Acute Pancreatitis ◽  
Nadph Oxidase ◽  
Interleukin 6 ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Dependent Manner ◽  
Ros Production ◽  
Ar42j Cells ◽  
Proinflammatory Mediators ◽  
Nadph Oxidase 1

Acute pancreatitis is a common clinical condition with increasing the proinflammatory mediators, including interleukin-6 (IL-6). Obesity is a negative prognostic factor in acute pancreatitis. Obese patients with acute pancreatitis have a higher systemic inflammatory response rate. Levels of serum resistin, an adipocytokine secreted by fat tissues, increase with obesity. Cerulein, a cholecystokinin analog, induces calcium (Ca2+) overload, oxidative stress, and IL-6 expression in pancreatic acinar cells, which are hallmarks of acute pancreatitis. A recent study showed that resistin aggravates the expression of inflammatory cytokines in cerulein-stimulated pancreatic acinar cells. We aimed to investigate whether resistin amplifies cerulein-induced IL-6 expression and whether astaxanthin (ASX), an antioxidant carotenoid with anti-inflammatory properties, inhibits ceruelin/resistin-induced IL-6 expression in pancreatic acinar AR42J cells. We found that resistin enhanced intracellular Ca2+ levels, NADPH oxidase activity, intracellular reactive oxygen species (ROS) production, NF-κB activity, and IL-6 expression in cerulein-stimulated AR42J cells, which were inhibited by ASX in a dose-dependent manner. The calcium chelator BAPTA-AM inhibited cerulein/resistin-induced NADPH oxidase activation and ROS production. Antioxidant N-acetyl cysteine (NAC) and ML171, a specific NADPH oxidase 1 inhibitor, suppressed cerulein/resistin-induced ROS production, NF-κB activation, and IL-6 expression. In conclusion, ASX inhibits IL-6 expression, by reducing Ca2+ overload, NADPH oxidase-mediated ROS production, and NF-κB activity in cerulein/resistin-stimulated pancreatic acinar cells. Consumption of ASX-rich foods could be beneficial for preventing or delaying the incidence of obesity-associated acute pancreatitis.

Synthesis and Biological Evaluation of Novel Heterocyclic Imines Linked Coumarin- Thiazole Hybrids as Anticancer Agents

2019 ◽  
Vol 19 (4) ◽  
pp. 557-566 ◽  
Author(s):  
Nerella S. Goud ◽  
Mahammad S. Ghouse ◽  
Jatoth Vishnu ◽  
Jakkula Pranay ◽  
Ravi Alvala ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Membrane Potential ◽  
Fluorescence Spectroscopy ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Annexin V ◽  
Biological Evaluation ◽  
Dependent Manner ◽  
Dapi Staining ◽  
Dose Dependent

Background: Human Galectin-1, a protein of lectin family showing affinity towards β-galactosides has emerged as a critical regulator of tumor progression and metastasis, by modulating diverse biological events including homotypic cell aggregation, migration, apoptosis, angiogenesis and immune escape. Therefore, galectin-1 inhibitors might represent novel therapeutic agents for cancer. Methods: A new series of heterocyclic imines linked coumarin-thiazole hybrids (6a-6r) was synthesized and evaluated for its cytotoxic potential against a panel of six human cancer cell lines namely, lung (A549), prostate (DU-145), breast (MCF-7 & MDA-MB-231), colon (HCT-15 & HT-29) using MTT assay. Characteristic apoptotic assays like DAPI staining, cell cycle, annexin V and Mitochondrial membrane potential studies were performed for the most active compound. Furthermore, Gal-1 inhibition was confirmed by ELISA and fluorescence spectroscopy. Results: Among all, compound 6g 3-(2-(2-(pyridin-2-ylmethylene) hydrazineyl) thiazol-4-yl)-2H-chromen-2- one exhibited promising growth inhibition against HCT-15 colorectal cancer cells with an IC50 value of 1.28 ± 0.14 µM. The characteristic apoptotic morphological features like chromatin condensation, membrane blebbing and apoptotic body formation were clearly observed with compound 6g on HCT-15 cells using DAPI staining studies. Further, annexin V-FITC/PI assay confirmed effective early apoptosis induction by treatment with compound 6g. Loss of mitochondrial membrane potential and enhanced ROS generation were confirmed with JC-1 and DCFDA staining method, respectively by treatment with compound 6g, suggesting a possible mechanism for inducing apoptosis. Moreover, flow cytometric analysis revealed that compound 6g blocked G0/G1 phase of the cell cycle in a dose-dependent manner. Compound 6g effectively reduced the levels of Gal-1 protein in a dose-dependent manner. The binding constant (Ka) of 6g with Gal-1 was calculated from the intercept value which was observed as 1.9 x 107 M-1 by Fluorescence spectroscopy. Molecular docking studies showed strong interactions of compound 6g with Gal-1 protein. Conclusion: Our studies demonstrate the anticancer potential and Gal-1 inhibition of heterocyclic imines linked coumarin-thiazole hybrids.

scholarly journals The Olive Leaves Extract Has Anti-Tumor Effects against Neuroblastoma through Inhibition of Cell Proliferation and Induction of Apoptosis

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2178
Author(s):  
Fabio Morandi ◽  
Veronica Bensa ◽  
Enzo Calarco ◽  
Fabio Pastorino ◽  
Patrizia Perri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Viability ◽  
Cell Cycle Progression ◽  
Treatment Strategies ◽  
Annexin V ◽  
Dependent Manner ◽  
Induction Of Apoptosis ◽  
Dose Dependent

Neuroblastoma (NB) is the most common extra-cranial solid tumor of pediatric age. The prognosis for high-risk NB patients remains poor, and new treatment strategies are desirable. The olive leaf extract (OLE) is constituted by phenolic compounds, whose health beneficial effects were reported. Here, the anti-tumor effects of OLE were investigated in vitro on a panel of NB cell lines in terms of (i) reduction of cell viability; (ii) inhibition of cell proliferation through cell cycle arrest; (iii) induction of apoptosis; and (iv) inhibition of cell migration. Furthermore, cytotoxicity experiments, by combining OLE with the chemotherapeutic topotecan, were also performed. OLE reduced the cell viability of NB cells in a time- and dose-dependent manner in 2D and 3D models. NB cells exposed to OLE underwent inhibition of cell proliferation, which was characterized by an arrest of the cell cycle progression in G0/G1 phase and by the accumulation of cells in the sub-G0 phase, which is peculiar of apoptotic death. This was confirmed by a dose-dependent increase of Annexin V+ cells (peculiar of apoptosis) and upregulation of caspases 3 and 7 protein levels. Moreover, OLE inhibited the migration of NB cells. Finally, the anti-tumor efficacy of the chemotherapeutic topotecan, in terms of cell viability reduction, was greatly enhanced by its combination with OLE. In conclusion, OLE has anti-tumor activity against NB by inhibiting cell proliferation and migration and by inducing apoptosis.

scholarly journals Tyrosine phosphorylation of guanosine triphosphatase activating protein by activation via surface IgG in human B cells

Blood ◽  
1993 ◽  
Vol 81 (6) ◽  
pp. 1535-1539
Author(s):  
H Yagura ◽  
N Oyaizu ◽  
S Pahwa
Keyword(s):  
B Cells ◽  
Tyrosine Phosphorylation ◽  
Signal Transduction Pathway ◽  
Dependent Manner ◽  
Transduction Pathway ◽  
Gtpase Activating Protein ◽  
Human B Cells ◽  
Associated Proteins ◽  
Guanosine Triphosphatase ◽  
Dose Dependent

In this study, we analyzed tyrosine phosphorylation of guanosine triphosphatase (GTPase) activating protein in human B cells stimulated through surface IgG, using Western blot and immunoprecipitation. Stimulation through surface IgG induced the tyrosine phosphorylation of GTPase-activating protein (GAP) and two associated proteins, a 190-Kd protein and a 62-Kd protein, within 1 minute and in a dose-dependent manner. This tyrosine phosphorylation was blocked by Genistein (Extrasynthese, Genay, France). These data suggest that GTPase- activating protein is involved in a signal transduction pathway initiated from surface IgG in human B cells.

Phosphoinositide synthesis in desensitized rat pancreatic acinar cells

1995 ◽  
Vol 268 (6) ◽  
pp. G1043-G1050
Author(s):  
J. S. Lods ◽  
B. Rossignol ◽  
C. Dreux ◽  
J. Morisset
Keyword(s):  
Phorbol Ester ◽  
Inositol Trisphosphate ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Basal Rate ◽  
Phosphoinositide Turnover ◽  
Dose Dependent

To help understand the possible role of phosphoinositide turnover in the desensitization process, the availability of phosphatidylinositol 4,5-bisphosphate was investigated in normal and desensitized pancreatic acinar cells treated with carbamylcholine (Cch), caerulein (Cae), and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). In control acini, incorporation of [myo-3H]inositol into total phosphoinositides was maximal at 120 min, was Cch and Cae dose dependent, and was insensitive to TPA. Cch stimulation increased the proportion of [myo-3H]inositol incorporated into phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], whereas Cae specifically channeled [myo-3H]inositol incorporation into phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. In the desensitized cells, preexposure to Cch and Cae, but not to TPA, increased the subsequent basal rate of [myo-3H]inositol incorporation into total phosphoinositol (PI) by 66 and 50% above control values. There were no subsequent responses to increasing concentrations of Cch, Cae, and TPA during a second incubation. Desensitization of the pancreatic secretory responses to Cch, Cae, and TPA does not seem to result from a decrease either in total PI or in specific PtdIns(4,5)P2 synthesis, which is needed for inositol trisphosphate and diacylglycerol production.

Hyperpolarizing effect of aminophylline, theophylline, and cAMP on rat diaphragm fibers

1988 ◽  
Vol 64 (5) ◽  
pp. 1893-1899 ◽  
Author(s):  
O. Delbono ◽  
B. A. Kotsias
Keyword(s):  
Normal Values ◽  
Bath Temperature ◽  
Resting Membrane Potential ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Rat Diaphragm ◽  
K Concentration ◽  
Dose Dependent ◽  
K Permeability

We studied the effect of aminophylline and theophylline (0.1–2 mM) on the resting membrane potential (Vm) of rat diaphragm fibers in vitro (25 degrees C). The main findings are the following. 1) Aminophylline and theophylline hyperpolarize the fibers in a dose-dependent manner. This effect is present with 0.1 and 0.25 mM of aminophylline and theophylline, respectively, and the maximum effect is reached with 1 mM of the drug (approximately 5–8 mV in comparison to the normal values). This effect is reversible by washing out the preparation with normal solution. 2) Dibutyryladenosine 3',5'-cyclic monophosphate (DBcAMP, 2 mM) produces a similar increment in the Vm. 3) The hyperpolarizing action observed in the presence of aminophylline, theophylline, and DBcAMP is suppressed by 5 X 10(-4) M ouabain or by lowering the bath temperature to 5 degrees C. These results suggest that the xanthines may directly or indirectly stimulate a Na-K pump. Two possibilities may be considered: 1) an electrogenic effect of the Na-K pump and 2) a reduction in the extracellular K+ concentration in the solution contacting the external side of the cell as a consequence of the activity of the Na-K pump. Alternative mechanisms such as a reduction in Na permeability or an increment in K permeability might collaborate in the hyperpolarizing effect of the drugs tested.

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