Benzimidazole derivatives protect against cytokine-induced apoptosis in pancreatic β-Cells

Zawawi, Nik Khairunissa Nik Abdullah; Rajput, Sajid Ali; Taha, Muhammad; Ahmat, Norizan; Ismail, Nor Hadiani; Abdullah, Noraishah; Khan, Khalid Mohammed; Choudhary, M. Iqbal

doi:10.1016/j.bmcl.2015.08.022

Cited by 12 publications

(6 citation statements)

References 31 publications

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“…Several studies have identified small molecule inhibitors of cytokine-induced beta cell apoptosis, such as histone deacetylases (HDACs) inhibitors, suberoylanilide hydroxamic acid (SAHA), and as trichostatin A (TSA) [33][34][35][36]. We have previously reported benzimidazole derivatives as suppressors of cytokineinduced beta cell death [25].…”

Section: Discussionmentioning

confidence: 99%

“…Ribonucleotide adenosine triphosphates (rATPs) (Promega) were used for the standard curve. In this study, we prepared a cytokine cocktail (20 ng/mL IL-1β, 50 ng/mL, IFN-γ, and 50 ng/mL TNF-α) to model the events leading to beta cell death as previously described [25]. INS-1E cells were seeded at 3 x 10 4 cells per well in white optical 96-well plates (Perkin Elmer, USA).…”

Section: Measurement Of the Cellular Atp Levelsmentioning

confidence: 99%

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Bergenin protects pancreatic beta cells against cytokine-induced apoptosis in INS-1E cells

2020

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Beta cell apoptosis induced by proinflammatory cytokines is one of the hallmarks of diabetes. Small molecules which can inhibit the cytokine-induced apoptosis could lead to new drug candidates that can be used in combination with existing therapeutic interventions against diabetes. The current study evaluated several effects of bergenin, an isocoumarin derivative, in beta cells in the presence of cytokines. These included (i) increase in beta cell viability (by measuring cellular ATP levels) (ii) suppression of beta cell apoptosis (by measuring caspase activity), (iii) improvement in beta cell function (by measuring glucose-stimulated insulin secretion), and (iv) improvement of beta cells mitochondrial physiological functions. The experiments were carried out using rat beta INS-1E cell line in the presence or absence of bergenin and a cocktail of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon- gamma) for 48 hr. Bergenin significantly inhibited beta cell apoptosis, as inferred from the reduction in the caspase-3 activity (IC50 = 7.29 ± 2.45 μM), and concurrently increased cellular ATP Levels (EC50 = 1.97 ± 0.47 μM). Bergenin also significantly enhanced insulin secretion (EC50 = 6.73 ± 2.15 μM) in INS-1E cells, presumably because of the decreased nitric oxide production (IC50 = 6.82 ± 2.83 μM). Bergenin restored mitochondrial membrane potential (EC50 = 2.27 ± 0.83 μM), decreased ROS production (IC50 = 14.63 ± 3.18 μM), and improved mitochondrial dehydrogenase activity (EC50 = 1.39 ± 0.62 μM). This study shows for the first time that bergenin protected beta cells from cytokine-induced apoptosis and restored insulin secretory function by virtue of its anti-inflammatory, antioxidant and anti-apoptotic properties. To sum up, the above mentioned data highlight bergenin as a promising anti-apoptotic agent in the context of diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Measurement Of the Cellular Atp Levelsmentioning

confidence: 99%

Bergenin protects pancreatic beta cells against cytokine-induced apoptosis in INS-1E cells

2020

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“…N-heterocycles are important integral pharmacophoric units ubiquitously used in a variety of biologically active natural products, agrochemicals, pharmaceutical and synthetic drugs (Khan et al, 2016). 2,3-Dihydroquinazolin-4(1H)-one plays an important role in the aromatic nitrogen-containing heterocycles because of their abundant pharmacological and biological activities (Kshirsagar, 2015;Zawawi et al, 2015;Dohle et al, 2018). Compounds containing this motif have shown significant biological activities which include anticancer, anticonvulsant, antidefibrillatory, analgesic, diuretic, antihistamine, antihypertensive, and many other activities (Patil et al, 2015;Zawawi et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…2,3-Dihydroquinazolin-4(1H)-one plays an important role in the aromatic nitrogen-containing heterocycles because of their abundant pharmacological and biological activities (Kshirsagar, 2015;Zawawi et al, 2015;Dohle et al, 2018). Compounds containing this motif have shown significant biological activities which include anticancer, anticonvulsant, antidefibrillatory, analgesic, diuretic, antihistamine, antihypertensive, and many other activities (Patil et al, 2015;Zawawi et al, 2015). These heterocycles participate in physiological processes as markers or messenger molecules and a large number of pharmaceuticals based on these heterocycles have been reported in the past few decades (Saeedi et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

An Aqueous Facile Synthesis of 2,3-Dihydroquinazolin-4(1H)-One Derivatives by Reverse Zinc Oxide Micelles as Nanoreactor

et al. 2020

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A green synthetic protocol has been developed for the efficient preparation of 2,3-dihydroquinazolin−4(1H)-one derivatives with excellent yield in aqueous media. Reverse zinc oxide micelles catalyzed the reactions efficiently and selectively as the hallow nanoreactor. Moreover, the catalyst was reusable without significant loss of catalytic efficiency. The notable advantages of the procedure are high yields and mild reaction conditions, simple operation, nonchromatographic purification, environmentally friendly and good versatile substrates.

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“…ESI-MS m/z 288 (MH + ); purity >95%.3-(5-Phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide(17). ESI-MS m/z 314 (MH + ); purity >95%.5-(5-Phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2amine(18). ESI-MS m/z 288 (MH + ); purity >95%.3-Iodo-5-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine (20, R 2 = ptolyl, CAS: 2099015-36-6).…”

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confidence: 99%

Discovery of 5-(3,4-Difluorophenyl)-3-(pyrazol-4-yl)-7-azaindole (GNF3809) for β-Cell Survival in Type 1 Diabetes

Huang

Tremblay

et al. 2019

ACS Omega

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Pancreatic β-cell apoptosis, a hallmark of the development of type 1 diabetes (T1D), is associated with increased levels of pro-inflammatory cytokines. Thus, an agent protecting β-cells from cytokine-induced stress should have an impact on maintaining functional β-cell mass in T1D. Screening of a ∼2 million-compound library identified a series of 7-azaindole derivatives as capable of protecting rat insulinoma β-cells from death induced by pro-inflammatory cytokines. The screening hits were optimized to result in GNF3809, a compound which preserves insulin content and viability of β-cells in both rodent and human islets under stress induced by cytokines. In vivo, orally bioavailable GNF3809 prevented elevated blood glucose level and improved oral glucose tolerance in a nonobese diabetic mouse model. This work lays the foundation for development of a new class of therapeutic interventions for T1D.

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Benzimidazole derivatives protect against cytokine-induced apoptosis in pancreatic β-Cells

Cited by 12 publications

References 31 publications

Bergenin protects pancreatic beta cells against cytokine-induced apoptosis in INS-1E cells

Bergenin protects pancreatic beta cells against cytokine-induced apoptosis in INS-1E cells

An Aqueous Facile Synthesis of 2,3-Dihydroquinazolin-4(1H)-One Derivatives by Reverse Zinc Oxide Micelles as Nanoreactor

Discovery of 5-(3,4-Difluorophenyl)-3-(pyrazol-4-yl)-7-azaindole (GNF3809) for β-Cell Survival in Type 1 Diabetes

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