scholarly journals Zurampic Protects Pancreatic β-Cells from High Uric Acid Induced-Damage by Inhibiting URAT1 and Inactivating the ROS/AMPK/ERK Pathways

2018 ◽  
Vol 47 (3) ◽  
pp. 1074-1083 ◽  
Author(s):  
Ying Xin ◽  
Kun Wang ◽  
Zhaotong Jia ◽  
Tao Xu ◽  
Qiang Xu ◽  
...  
Keyword(s):  
Uric Acid ◽  
Cell Viability ◽  
Mrna Expression ◽  
Caspase 3 ◽  
Dependent Manner ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Underlying Mechanisms ◽  
High Level ◽  
High Uric Acid

Background/Aims: Zurampic is a US FDA approved drug for treatment of gout. However, the influence of Zurampic on pancreatic β-cells remains unclear. The study aimed to evaluate the effects of Zurampic on high uric acid-induced damage of pancreatic β-cells and the possible underlying mechanisms. Methods: INS-1 cells and primary rat islets were stimulated with Zurampic and the mRNA expression of urate transporter 1 (URAT1) was assessed by qRT-PCR. Cells were stimulated with uric acid or uric acid plus Zurampic, and cell viability, apoptosis and ROS release were measured by MTT and flow cytometry assays. Western blot analysis was performed to evaluate the expressions of active Caspase-3 and phosphorylation of AMPK and ERK. Finally, cells were stimulated with uric acid or uric acid plus Zurampic at low/high level of glucose (2.8/16.7 mM glucose), and the insulin release was assessed by ELISA. Results: mRNA expression of URAT1 was decreased by Zurampic in a dose-dependent manner. Uric acid decreased cell viability, promoted cell apoptosis and induced ROS release. Uric acid-induced alterations could be reversed by Zurampic. Activation of Caspase-3 and phosphorylation of AMPK and ERK were enhanced by uric acid, and the enhancements were reversed by Zurampic. Decreased phosphorylation of AMPK and ERK, induced by Zurampic, was further reduced by adding inhibitor of AMPK or ERK. Besides, uric acid inhibited high glucose-induced insulin secretion and the inhibition was rescued by Zurampic. Conclusions: Zurampic has a protective effect on pancreatic β-cells against uric acid induced-damage by inhibiting URAT1 and inactivating the ROS/AMPK/ERK pathway.

scholarly journals Antioxidant activity of a new multiflorane-type triterpene from seeds of Cucurbita Argyrosperma and their protective role on hydrogen peroxide induced oxidative stress

2020 ◽  
Vol 10 (2) ◽  
pp. 95
Author(s):  
Rosa Martha Perez Gutierrez ◽  
Alethia Muñiz Ramirez ◽  
Jose Maria Mota Flores ◽  
Abraham Heriberto Garcia Campoy
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Free Radical ◽  
Cell Viability ◽  
Caspase 3 ◽  
Radical Scavenging ◽  
Free Radical Scavenging ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Background: Cucurbita Argyrosperma seeds have acquired a reputation as an herbal remedy to treat various diseases because this plant is a predominant source of natural compounds with potent anti-inflammatory, antioxidant properties, and seed supplementation improves oxidative stress. Previous studies indicated that an imbalance between H2O2 production and elimination capacity is responsible for β-cell vulnerability, making β-cell a target susceptible to pathological disasters.This investigation aimed to evaluate the protective effects of one new multiflorane-type triterpene  3β-trans-caffeoyloxymultiflor-8-ene- 7α,12β, 18 β-triol (1)  from MeOH extract from C. Argyrosperma, on rat pancreatic β cells (INS-1 cells) exposed to hydrogen peroxide (H2O2) induced oxidative stress conditions.Methods: The chemical structure of the novel triterpene, which was identified as 3β-trans-caffeoyloxymultiflor-8-ene- 7α,12β, 18 β-triol (1), was established based on the interpretation of spectroscopic analyses. The antioxidant activities of 1 were leaded by detect radical scavenging potential of 2,2-dyphenyl-1-picrylhydrazyl (DPPH) and 3.1 2,2′-Azino-bis(3-Ethylbenzothiazoline-6-Sulfonic Acid) ABTS. The assays were conducted on INS-1 cells line exposed to increasing concentrations of 1 at 5,10 and 20 µg/mL and H2O2 at 250 µM. Then, the experiments, cell viability, cell integrity ((LDH; lactate dehydrogenase release), mitochondrial function (ATP analysis), ROS formation, lipid peroxidation (MDA) and caspase-3, 9 activities were measured in the cells. We also determined the effect of 1 on antioxidant enzyme levels and cytotoxicity in pancreatic β cells under oxidant conditions.Results: The results showed that triterpene displayed high free-radical-scavenging activity, which is similar to that of standard antioxidants used. At concentrations of 5, 10, and 20 𝜇g/mL protect INS-1 cells against H2O2 induced cytotoxicity decrease in cell death, with a marked increase in cell viability, sustained cellular functionality (ATP). Antioxidant enzymes such as glutathione peroxidase (GPx), glutathione reduced (GSH), catalase (CAT), superoxide dismutase (SOD), and the non-antioxidant enzyme (GSH) increased in INS-1 cells with 1 pretreatment. MDA in pancreatic cells was ameliorated by 1 pretreatment reducing intracellular reactive oxygen species level. Findings also demonstrated that H2O2-induced apoptosis in INS-1 cells and produced modulation of the caspase-3, 9 expressions in INS-1 cells exposed to 1. Exposure to 1significantly inhibited ROS and apoptosis production, reducing β cell dysfunction under oxidant conditions.Conclusions: Triterpene consequently could be a promising natural antioxidant for use in maintaining the integrity of pancreatic β-cells exposed to oxidative stress conditions being able to participate in the control type 2 diabetes.Keywords: Cucurbita Argyrosperma; antioxidants; multiflorane; free radical scavenging: oxidative stress

Uptake of nicotinamide by rat pancreatic β cells with regard to streptozotocin action

1991 ◽  
Vol 131 (1) ◽  
pp. 135-138 ◽  
Author(s):  
M. Sofue ◽  
Y. Yoshimura ◽  
M. Nishida ◽  
J. Kawada
Keyword(s):  
Cell Viability ◽  
Succinic Dehydrogenase ◽  
Facilitated Diffusion ◽  
Dependent Manner ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Intracellular Atp ◽  
Atp Concentration ◽  
Dose Dependent Decrease ◽  
Dose Dependent

ABSTRACT Exposure of rat pancreatic β cells in monolayer culture to 2 mmol streptozotocin (STZ)/1 for 1 h followed by thorough washing inhibited their uptake of [14C]nicotinamide and [3H]2-deoxyglucose ([2H]2-DG) to about 50% and also reduced the intracellular ATP concentration to 50% of that in control cells. These changes were not due to a lethal cytotoxic effect of STZ, because cell viability, as estimated by succinic dehydrogenase activity, was 90% of that of control cells. Oligomycin and carbonylcyanide-m-chlorophenylhydrazone (CCCP), an uncoupler of oxidative phosphorylation, caused a dose-dependent decrease in intracellular ATP concentration while maintaining high cell viability. These ATP-depleted cells showed a decrease in insulin release and an inhibition of the uptake of [14C]nicotinamide and [3H]2-DG in a dose-dependent manner. Therefore oligomycin and CCCP reproduced the same effects as those found in β cells treated with STZ. These results suggest that the uptake of nicotinamide and 2-DG by β cells might be regulated by their intracellular ATP concentration. The decreased uptake of nicotinamide in ATP-depleted β cells caused by STZ might explain the lack of protective effect of nicotinamide against STZ cytotoxicity when administered after the latter. Furthermore, the radiotracer experiments demonstrated that the transport of nicotinamide by intact β cells was inhibited in a dose-dependent manner by 2-DG and vice versa, i.e. the transport of 2-DG was inhibited by nicotinamide. These findings suggest the existence of a common transport mechanism in β cells responsible for the uptake of nicotinamide and 2-DG, the transport of which is known to occur by facilitated diffusion. Journal of Endocrinology (1991) 131, 135–138

scholarly journals Rule of UA on Cardiac Myocytes Uric Acid Differently Influence the Oxidative Damage Induced by Acute Exposure of High Level of Glucose in Chicken Cardiac Myocytes

2020 ◽  
Vol 7 ◽  
Author(s):  
Xiaolong Sun ◽  
Hongchao Jiao ◽  
Jingpeng Zhao ◽  
Xiaojuan Wang ◽  
Hai Lin
Keyword(s):  
Uric Acid ◽  
Oxidative Damage ◽  
Cell Viability ◽  
Cardiac Myocytes ◽  
High Glucose ◽  
Acute Exposure ◽  
Related Factor ◽  
Mrna Levels ◽  
Dependent Manner ◽  
High Level

Background: Uric acid (UA) is a potent scavenger of oxidants in mammalian and avian species. In humans, hyperglycemia with simultaneous hyperuricemia may exert additional damage to the cardiovascular system. Chickens naturally have hyperglycemia (10.1–11.0 mmol/L) and hyperuricemia (100–900 μmol/L), which makes them an interesting model.Methods: The aim of this study was to investigate the effects of UA on the oxidative damage induced by acute exposure of high level of glucose in chicken cardiac myocytes.Results: Cell viability and the concentrations of thiobarbituric acid reactive substance (TBARS) were decreased by glucose treatment in a dose- and time-dependent manner. After acute exposure to high level of glucose (300 mM), a moderate level of UA (300 μM) increased cell viability and reduced TBARS and glutathione (GSH) content. Compared to the control or to independent high glucose (300 mM) or UA (1,200 μM) treatment, the concurrent treatment of high glucose and high UA significantly increased the TBARS, protein carbonyl contents, and ROS concentration, whereas it decreased the cell viability, superoxide dismutase (SOD) activity, and GSH content. In the presence of high glucose and UA, the nucleic protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was decreased and the mRNA levels of the genes cat, sod1, sod2, gss, and gclc were downregulated.Conclusion: In conclusion, acute exposure of high level of glucose induced oxidative damage in the cardiac myocytes of chicken. The present result suggests that an adequate level of uric acid is helpful in alleviating the acute oxidative damage that is induced by high glucose, whereas the inhibition of the Nrf2 pathway by a high level of uric acid may render the cardiac myocytes more vulnerable to suffering from oxidative damage.

High uric acid promotes dysfunction in pancreatic β cells by blocking IRS2/AKT signalling

2021 ◽  
Vol 520 ◽  
pp. 111070
Author(s):  
Yaqiu Hu ◽  
Hairong Zhao ◽  
Jiaming Lu ◽  
De Xie ◽  
Qiang Wang ◽  
...  
Keyword(s):  
Uric Acid ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
High Uric Acid

scholarly journals HM-Chromanone Isolated from Portulaca oleracea L. Protects INS-1 Pancreatic β Cells against Glucotoxicity-Induced Apoptosis

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 404 ◽  
Author(s):  
Jae Eun Park ◽  
Youngwan Seo ◽  
Ji Sook Han
Keyword(s):  
Protein Expression ◽  
Cell Viability ◽  
High Glucose ◽  
Annexin V ◽  
Thiobarbituric Acid ◽  
Portulaca Oleracea ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Induced Apoptosis ◽  
High Level

In this study, we investigated whether (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone, a homoisoflavonoid compound isolated from Portulaca oleracea L., protects INS-1 pancreatic β cells against glucotoxicity-induced apoptosis. Treatment with high glucose (30 mM) induced apoptosis in INS-1 pancreatic β cells; however, the level of cell viability was significantly increased by treatment with (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone. Treatment with 10–20 µM of (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone dose-dependently increased cell viability and significantly decreased the intracellular level of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), and nitric oxide levels in INS-1 pancreatic β cells pretreated with high glucose. These effects were associated with increased anti-apoptotic Bcl-2 protein expression, while reducing pro-apoptotic Bax, cytochrome C, and caspase 9 protein expression. Treatment with (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone reduced the apoptosis previously induced by high-level glucose-treatment, according to annexin V/propidium iodide staining. These results demonstrate that (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone may be useful as a potential therapeutic agent to protect INS-1 pancreatic β cells against high glucose-induced apoptosis.

scholarly journals Inhibition of Prenylation Promotes Caspase 3 Activation, Lamin B Degradation and Loss in Metabolic Cell Viability in Pancreatic β-Cells

2017 ◽  
Vol 43 (3) ◽  
pp. 1052-1063 ◽  
Author(s):  
Khadija G. Syeda ◽  
Anjan Kowluru
Keyword(s):  
Cell Viability ◽  
Caspase 3 ◽  
Cell Function ◽  
Protein Prenylation ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Intermediate Filament Proteins ◽  
Lamin B ◽  
Metabolic Defects ◽  
Cell Proliferation Inhibition

Background/Aims: Lamins are intermediate filament proteins that constitute the main components of the lamina underlying the inner-nuclear membrane and serve to organize chromatin. Lamins (e.g., lamin B) undergo posttranslational modifications (e.g., isoprenylation) at their C-terminal cysteine residues. Such modifications are thought to render optimal association of lamins with the nuclear envelop. Using human islets, rodent islets, and INS-1 832/13 cells, we recently reported significant metabolic defects under glucotoxic and endoplasmic reticulum (ER) stress conditions, including caspase 3 activation and lamin B degradation. The current study is aimed at further understanding the regulatory roles of protein prenylation in the induction of the aforestated metabolic defects. Methods: Subcellular phase partitioning assay was done using Triton X-114. Cell morphology and metabolic cell viability assays were carried out using standard methodologies. Results: We report that exposure of pancreatic β-cells to Simvastatin, an inhibitor of mevalonic acid (MVA) biosynthesis, and its downstream isoprenoid derivatives, or FTI-277, an inhibitor of farnesyltransferase that mediates farnesylation of lamins, leads to activation of caspase 3 and lamin B degradation. Furthermore, Simvastatin-treatment increased activation of p38MAPK (a stress kinase) and inhibited ERK1/2 (regulator of cell proliferation). Inhibition of farnesylation also resulted in the release of degraded lamin B into the cytosolic fraction and promoted loss in metabolic cell viability. Conclusion: Based on these findings we conclude that protein prenylation plays key roles in islet β-cell function. These findings affirm further support to the hypothesis that defects in prenylation pathway induce caspase-3 activation and nuclear lamin degradation in pancreatic β-cells under the duress of metabolic stress (e.g., glucotoxicity).

The Effects of Butyric Acid on the Differentiation, Proliferation, Apoptosis, and Autophagy of IPEC-J2 Cells

2020 ◽  
Vol 20 (4) ◽  
pp. 307-317
Author(s):  
Yuan Yang ◽  
Jin Huang ◽  
Jianzhong Li ◽  
Huansheng Yang ◽  
Yulong Yin
Keyword(s):  
Cell Viability ◽  
P38 Mapk ◽  
Butyric Acid ◽  
Cell Apoptosis ◽  
Mapk Pathway ◽  
Mrna Level ◽  
Dependent Manner ◽  
M Phase ◽  
High Concentrations ◽  
Underlying Mechanisms

Background: Butyric acid (BT), a short-chain fatty acid, is the preferred colonocyte energy source. The effects of BT on the differentiation, proliferation, and apoptosis of small intestinal epithelial cells of piglets and its underlying mechanisms have not been fully elucidated. Methods: In this study, it was found that 0.2-0.4 mM BT promoted the differentiation of procine jejunal epithelial (IPEC-J2) cells. BT at 0.5 mM or higher concentrations significantly impaired cell viability in a dose- and time-dependent manner. In addition, BT at high concentrations inhibited the IPEC-J2 cell proliferation and induced cell cycle arrest in the G2/M phase. Results: Our results demonstrated that BT triggered IPEC-J2 cell apoptosis via the caspase8-caspase3 pathway accompanied by excess reactive oxygen species (ROS) and TNF-α production. BT at high concentrations inhibited cell autophagy associated with increased lysosome formation. It was found that BT-reduced IPEC-J2 cell viability could be attenuated by p38 MAPK inhibitor SB202190. Moreover, SB202190 attenuated BT-increased p38 MAPK target DDIT3 mRNA level and V-ATPase mRNA level that were responsible for normal acidic lysosomes. Conclusion: In conclusion, 1) at 0.2-0.4 mM, BT promotes the differentiation of IPEC-J2 cells; 2) BT at 0.5 mM or higher concentrations induces cell apoptosis via the p38 MAPK pathway; 3) BT inhibits cells autophagy and promotes lysosome formation at high concentrations.

Uric acid may inhibit glucose-induced insulin secretion via binding to an essential arginine residue in rat pancreatic β-cells

2005 ◽  
Vol 15 (4) ◽  
pp. 1181-1184 ◽  
Author(s):  
Boris Ročić ◽  
Marijana Vučić-Lovrenčić ◽  
Nevenka Poje ◽  
Mirko Poje ◽  
Federico Bertuzzi
Keyword(s):  
Uric Acid ◽  
Insulin Secretion ◽  
Arginine Residue ◽  
Β Cells ◽  
Pancreatic Β Cells
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