scholarly journals Glutaric Acid-Mediated Apoptosis in Primary Striatal Neurons

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Fengyan Tian ◽  
Xi Fu ◽  
Jinzhi Gao ◽  
Yanqin Ying ◽  
Ling Hou ◽  
...  
Keyword(s):  
Glutaric Acid ◽  
Caspase 3 ◽  
Neuronal Damage ◽  
Annexin V ◽  
Nmda Receptor Antagonist ◽  
Glutaric Aciduria Type ◽  
Type I ◽  
Striatal Neurons ◽  
Apoptotic Pathway ◽  
Transmission Electron

Glutaric acid (GA) has been implicated in the mechanism of neurodegeneration in glutaric aciduria type I. In the present study, the potential cytotoxic effects of GA (0.1~50 mM for 24~96 h) were examined in cultured primary rat striatal neurons. Results showed increase in the number of cells labeled by annexin-V or with apoptotic features shown by Hoechst/PI staining and transmission electron microscopy (TEM) and upregulation of the expression of mRNA as well as the active protein fragments caspase 3, suggesting involvement of the caspase 3-dependent apoptotic pathway in GA-induced striatal neuronal death. This effect was in part suppressed by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 but not theα-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonist 6-cyano-7-nitroquinoxalone-2,3-dione (CNQX). Thus, GA may trigger neuronal damage partially through apoptotic pathway and via activation of NMDA receptors in cultured primary striatal neurons.

scholarly journals Determinants of Monocyte Apoptosis in Cardiorenal Syndrome Type 1

2018 ◽  
Vol 8 (3) ◽  
pp. 208-216 ◽  
Author(s):  
Andrea Breglia ◽  
Grazia Maria Virzì ◽  
Silvia Pastori ◽  
Alessandra Brocca ◽  
Massimo de Cal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Caspase 3 ◽  
Kidney Injury ◽  
Annexin V ◽  
Cardiorenal Syndrome ◽  
Pathophysiological Mechanism ◽  
Syndrome Type ◽  
Caspase 9 ◽  
Apoptotic Pathway

Background: Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Its pathophysiology is complex and not completely understood. In this study, we examined the role of apoptosis and the caspase pathways involved. Material and Methods: We enrolled 40 acute heart failure (AHF) patients, 11 of whom developed AKI characterizing CRS type 1. We exposed the human cell line U937 to plasma from the CRS type 1 and AHF groups and then we evaluated apoptotic activity by annexin-V evaluation, determination of caspase-3, -8 and -9 levels, and BAX, BAD, and FAS gene expression. Results: We observed significant upregulation of apoptosis in monocytes exposed to CRS type 1 plasma compared to AHF, with increased levels of caspase-3 (p < 0.01), caspase-9 (p < 0.01), and caspase-8 (p < 0.03) showing activation of both intrinsic and extrinsic pathways. Furthermore, monocytes exposed to CRS type 1 plasma had increased gene expression of BAX and BAD (intrinsic pathways) (p = 0.010 for both). Furthermore, strong significant correlations between the caspase-9 levels and BAD and BAX gene expression were observed (Spearman ρ = – 0.76, p = 0.011, and ρ = – 0.72, p = 0.011). Conclusion: CRS type 1 induces dual apoptotic pathway activation in monocytes; the two pathways converged on caspase-3. Many factors may induce activation of both intrinsic and extrinsic apoptotic pathways in CRS type 1 patients, such as upregulation of proinflammatory cytokines and hypoxia/ischemia. Further investigations are necessary to corroborate the present findings, and to better understand the pathophysiological mechanism and consequent therapeutic and prognostic implications for CRS type 1.

scholarly journals The Protective Effect of Fluorofenidone against Cyclosporine A-Induced Nephrotoxicity

2019 ◽  
Vol 44 (4) ◽  
pp. 656-668 ◽  
Author(s):  
Yang Chen ◽  
Nasui Wang ◽  
Qiongjing Yuan ◽  
Jiao  Qin ◽  
Gaoyun Hu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cyclosporine A ◽  
Caspase 3 ◽  
Renal Tubule ◽  
Annexin V ◽  
Type I ◽  
Tubulointerstitial Injury ◽  
Tubule Cells ◽  
Parp 1 ◽  
Tgf Β1

Background/Aims: Cyclosporine A (CsA) is an immunosuppressant drug that is used during organ transplants. However, its utility is limited by its nephrotoxic potential. This study aimed to investigate whether fluorofenidone (AKF-PD) could provide protection against CsA-induced nephrotoxicity. Methods: Eighty-five male Sprague-Dawley rats were divided into 5 groups: drug solvent, CsA, CsA with AKF-PD (250, 500 mg/kg/day), and CsA with pirfenidone (PFD, 250 mg/kg/day). Tubulointerstitial injury index, extracellular matrix (ECM) deposition, expression of type I and IV collagen, transforming growth factor (TGF)-β1, platelet-derived growth factor (PDGF), Fas ligand (FASL), cleaved-caspase-3, cleaved-poly(ADP-ribose) polymerase (PARP)-1, and the number of transferase-mediated nick end-labeling (TUNEL)-positive renal tubule cells were determined. In addition, levels of TGF-β1, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of annexin V-positive cells were determined in rat proximal tubular epithelial cells (NRK-52E) treated with CsA (20 μmol/L), AKF-PD (400 μg/mL), PFD (400 μg/mL), and GW788388 (5 μmol/L). Results: AKF-PD (250, 500 mg/kg/day) significantly reduced tubulointerstitial injury, ECM deposition, expression of type I and IV collagen, TGF-β1, PDGF, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of TUNEL-positive renal tubule cells in the CsA-treated kidneys. In addition, AKF-PD (400 μg/mL) significantly decreased TGF-β1, FASL, cleaved-caspase-3, and PARP-1 expression in NRK-52E cells and further reduced the number of annexin V-positive cells. Conclusion: AKF-PD protect kidney from fibrosis and apoptosis in CsA-induced kidney injury.

Inhibition of hypoxia/reoxygenation-induced apoptosis in metallothionein-overexpressing cardiomyocytes

2001 ◽  
Vol 280 (5) ◽  
pp. H2292-H2299 ◽  
Author(s):  
Guang-Wu Wang ◽  
Zhanxiang Zhou ◽  
Jon B. Klein ◽  
Y. James Kang
Keyword(s):  
Cytochrome C ◽  
Caspase 3 ◽  
Ischemia Reperfusion ◽  
Annexin V ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
Fetal Bovine ◽  
Induced Apoptosis ◽  
Hypoxia Reoxygenation

To study possible mechanisms for metallothionein (MT) inhibition of ischemia-reperfusion-induced myocardial injury, cardiomyocytes isolated from MT-overexpressing transgenic neonatal mouse hearts and nontransgenic controls were subjected to 4 h of hypoxia (5% CO2-95% N2, glucose-free modified Tyrode's solution) followed by 1 h of reoxygenation in MEM + 20% fetal bovine serum (FBS) (5% CO2-95% air), and cytochrome c-mediated caspase-3 activation apoptotic pathway was determined. Hypoxia/reoxygenation-induced apoptosis was significantly suppressed in MT-overexpressing cardiomyocytes, as measured by both terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling and annexin V-FITC binding. In association with apoptosis, mitochondrial cytochrome c release, as determined by Western blot, was observed to occur in nontransgenic cardiomyocytes. Correspondingly, caspase-3 was activated as determined by laser confocal microscopic examination with the use of FITC-conjugated antibody against active caspase-3 and by enzymatic assay. The activation of this apoptotic pathway was significantly inhibited in MT-overexpressing cells, as evidenced by both suppression of cytochrome c release and inhibition of caspase-3 activation. The results demonstrate that MT suppresses hypoxia/reoxygenation-induced cardiomyocyte apoptosis through, at least in part, inhibition of cytochrome c-mediated caspase-3 activation.

scholarly journals Mitigation of H2O2-Induced Mitochondrial-Mediated Apoptosis in NG108-15 Cells by Novel Mesuagenin C fromMesua kunstleri(King) Kosterm

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Gomathi Chan ◽  
Muhamad Noor Alfarizal Kamarudin ◽  
Daniel Zin Hua Wong ◽  
Nor Hadiani Ismail ◽  
Faizuri Abdul Latif ◽  
...  
Keyword(s):  
Cell Viability ◽  
Caspase 3 ◽  
Chromatin Condensation ◽  
Annexin V ◽  
Data Interpretation ◽  
Hexane Extract ◽  
Neuroprotective Activity ◽  
Apoptotic Pathway ◽  
Chemical Structures ◽  
Induced Apoptosis

This study was aimed to isolate and evaluate neuroprotective compounds from the hexane extract of the bark ofMesua kunstleri(Clusiaceae) on H2O2-induced apoptosis in NG108-15 cells. Five 4-phenylcoumarins were isolated by using various chromatographic techniques via neuroprotective activity-guided fractionation and isolation from the active hexane extract. The chemical structures of the isolated compounds were confirmed by NMR spectroscopic data interpretation and comparison with literature values. Cell viability data demonstrated that mesuagenin C3significantly increased cell viability. Hoechst 33342/PI staining illustrated mesuagenin C3was able to abate the nuclear shrinkage, chromatin condensation and formation of apoptotic bodies. Pretreatment with mesuagenin C3reduced total annexin V positive cells and increased the level of intracellular glutathione (GSH). Mesuagenin C3attenuated membrane potential (Δψm), reduced Bax/Bcl-2 ratio and inactivated of caspase-3/7 and -9. These results indicated that mesuagenin C3could protect NG108-15 cells against H2O2-induced apoptosis by increasing intracellular GSH level, aggrandizingΔψm, and modulating apoptotic signalling pathway through Bcl-2 family and caspase-3/7 and -9. These findings confirmed the involvement of intrinsic apoptotic pathway in H2O2-induced apoptosis and suggested that mesuagenin C3may have potential therapeutic properties for neurodegenerative diseases.

scholarly journals Apo2L/TRAIL and Bcl-2–related proteins regulate type I interferon–induced apoptosis in multiple myeloma

Blood ◽  
2001 ◽  
Vol 98 (7) ◽  
pp. 2183-2192 ◽  
Author(s):  
Quan Chen ◽  
Bendi Gong ◽  
Ashraf S. Mahmoud-Ahmed ◽  
Aimin Zhou ◽  
Eric D. Hsi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cytochrome C ◽  
Plasma Cells ◽  
Annexin V ◽  
Dominant Negative ◽  
Type I ◽  
Dependent Manner ◽  
Cytochrome C Release ◽  
Apoptotic Pathway

It has been reported that interferons (IFNs) may have antitumor activity in multiple myeloma (MM). The mechanism for their effect on MM, however, remains elusive. This study shows that IFN-α and -β, but not -γ, induce apoptosis characterized by Annexin V positivity, nuclear fragmentation and condensation, and loss of clonogenicity in 3 MM cell lines (U266, RPMI-8266, and NCI-H929), and in plasma cells from 10 patients with MM. Apo2 ligand (Apo2L, also TRAIL) induction was one of the earliest events following IFN administration in U266 cells. Treatment of these cells with TRAIL, but not with Fas agonistic antibodies, induces apoptosis. Cell death induced by IFNs and Apo2L in U266 cells was partially blocked by a dominant-negative Apo2L receptor, DR5, demonstrating the functional significance of Apo2L induction. This study shows that IFNs activate caspases and the mitochondrial-dependent apoptotic pathway, possibly mediated by Apo2L production. Thus, IFN-α and -β induce cytochrome c release from mitochondria starting at 12 hours, with an amplified release seen at 48 hours. Moreover, Bid cleavage precedes the initial cytochrome c release, whereas the late, amplified cytochrome c release coincides with changes in levels of Bcl-2, Bcl-XL, and reduction of mitochondrial membrane potential. These results link the Apo2L induction and modulation of Bcl-2 family proteins to mitochondrial dysfunction. Furthermore, IFNs and Apo2L induce cell death of CD38+/CD45−/dimplasma cells, without significant effect on nonplasma blood cells, in a caspase and Bcl-2 cleavage-dependent manner. These results warrant further clinical studies with IFNs and Apo2L in MM.

scholarly journals Controlled Release of Ursodeoxycholic Acid from Pullulan Acetate Nanoparticles to Modulate Glutamate-Induced Excitotoxicity in PC-12 Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Kwang Sik Yu ◽  
Jun Young Oh ◽  
Min Cheol Kim ◽  
Seong Hee Kang ◽  
Nam Seob Lee ◽  
...  
Keyword(s):  
Ursodeoxycholic Acid ◽  
Neuronal Damage ◽  
Annexin V ◽  
In Vitro Study ◽  
Poly Vinyl Alcohol ◽  
Neuroprotective Effects ◽  
Transmission Electron ◽  
Pullulan Acetate ◽  
Related Proteins

The neuroprotective effects of the ursodeoxycholic acid- (UDCA-) loaded pullulan acetate (PA) (UDCA-PA) nanospheres stabilized by poly(vinyl alcohol) (PVA) were identified by in vitro study. The UDCA-PA nanospheres were constructed by nanoemulsion process. The UDCA-PA nanospheres were analyzed using Fourier transform-infrared spectroscopy (FT-IR) and transmission electron microscopy (TEM). Then, the UDCA-PA nanospheres were used to treat PC-12 neuronal cells, which were formerly triggered by glutamate-induced excitotoxicity. As a result, the cells treated with the UDCA-PA nanospheres showed higher survival rate against glutamate-induced excitotoxicity. Furthermore, the UDCA-PA nanospheres decreased immunoreactivity of Annexin V, a membrane marker for apoptotic cells, in PC-12 with glutamate-induced injury. Particularly, the UDCA-PA nanospheres decreased the level of apoptosis-related proteins such as caspase-3. Taken together, the UDCA-PA nanospheres increased neuroprotective effects against glutamate-induced neuronal damage via inhibition of apoptosis at low concentration.

Inhibition of the Human Double Minute (HDM)-2 E3 Ubiquitin Ligase Activates Different Programmed Cell Death (PCD) Pathways in Models of Non-Hodgkin Lymphoma (NHL) with Wild Type (wt) and Mutant (mut) p53

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3618-3618 ◽  
Author(s):  
Richard Julian Jones ◽  
Janine Arts ◽  
Robert Z Orlowski
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Drug Exposure ◽  
Caspase 3 ◽  
Annexin V ◽  
Type I ◽  
Type Ii ◽  
Inhibition Of Proliferation ◽  
Acridine Orange Staining ◽  
The Impact

Abstract Background: The ubiquitin-proteasome pathway has been validated as a target for NHL with the recent approval of bortezomib for mantle cell lymphoma (MCL). In addition to anti-tumor activity, however, proteasome inhibitors have pleiotropic effects, including activation of anti-apoptotic heat shock proteins, and their use clinically is complicated by toxicities such as peripheral neuropathy. By targeting E3 ubiquitin ligases, which are involved in ubiquitination of only a small subset of cellular proteins, it may be possible to achieve more specific anti-tumor effects with a better therapeutic index. One attractive target is HDM-2, which is responsible for ubiquitination of the p53 tumor suppressor. Methods: To evaluate the therapeutic potential of agents targeting HDM-2, we studied the impact of the small molecule JNJ-26854165, an inhibitor of HDM-2-function, in both p53 wt and mut cell line models. Results: Treatment of wt p53 NHL cell lines with JNJ-26854165 induced a dose- and time-dependent inhibition of proliferation, with an IC50 in the 0.02–0.3 μM range. Cell death, which was typically seen within 48 hours of HDM-2 inhibition, occurred through induction of type I PCD, as judged by the appearance of increased staining with Annexin V and activation of caspase 3. While cell lines with mut p53 were generally less sensitive than their wt p53 counterparts, JNJ-26854165 remained potent, with an IC50 in the 0.05–0.6 μM range. The latter cell lines showed a longer kinetics of death, with PCD being seen within 72 hours of drug exposure. Notably, in these mut p53 cell lines, very little Annexin V staining or caspase 3 activation was seen, consistent with a minor role for type I PCD. Instead, mut p53 cell lines demonstrated an increased content of acidic vacuoles by acridine orange staining, increased expression of Beclin 1 and Sequestosome 1/p62, and conversion of microtubule-associated protein 1 light chain 3 form I to form II, consistent with activation of type II PCD, or autophagy. Also, electron microscopy showed an increased presence of autophagosomes and autolysosomes, further supporting the activation of this pathway. Combinations of JNJ-26854165 with other agents, including rapamycin, doxorubicin, and an inhibitor of Bcl 2, showed enhanced anti-proliferative effects in a sequence-dependent fashion, which were greatest when the chemotherapeutic preceded the HDM-2 inhibitor. Combination index analysis revealed that these interactions met criteria for synergy. Conclusions: Inhibition of the function of HDM-2 using JNJ-26854165 is a promising approach that is effective against both wt and mut p53 models by activating type I and type II PCD, respectively. The effectiveness of JNJ-26854165 was enhanced in combination with currently used chemotherapeutics in a sequence specific manner, providing a rationale for translation of this novel approach into the clinic.

Dihydroartemisinin induces ER stress-dependent apoptosis of Echinococcus protoscoleces in vitro

2020 ◽  
Vol 52 (10) ◽  
pp. 1140-1147
Author(s):  
Rongji Ma ◽  
Wenjuan Qin ◽  
Yuanmao Xie ◽  
Ziwei Han ◽  
Shuojie Li ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Er Stress ◽  
Caspase 3 ◽  
Morphological Changes ◽  
Apoptotic Pathway ◽  
Homologous Protein ◽  
Caspase 12 ◽  
Transmission Electron ◽  
Stress Dependent

Abstract In this study, we investigated the effect of dihydroartemisinin on Echinococcus protoscoleces and explored the role of endoplasmic reticulum stress in this process. Echinococcus protoscoleces were collected and cultured in RPMI 1640 medium. Changes in the expressions of glucose-regulated protein 78 (GRP-78), caspase-12, and C/EBP homologous protein (CHOP) were assessed through confocal immunofluorescence and western blot analysis. Cell viability and morphological changes were observed under a light microscope. The ultrastructure of protoscoleces was observed by scanning electron microscopy and transmission electron microscopy. Caspase-3 activity was detected using an enzyme assay kit. After dihydroartemisinin treatment, the protoscoleces showed loss of viability, and morphological changes including soma contraction, blebs formation, hooks loss, microtrichia destruction, and development of lipid droplets was observed. The levels of caspase-12 and CHOP were increased within 2 days of dihydroartemisinin treatment. However, the levels of GRP-78, caspase-12, and CHOP were decreased in 4 days. Furthermore, caspase-3 activity was increased after treatment with different concentrations of dihydroartemisinin. Dihydroartemisinin can induce apoptosis in protoscoleces via the ER stress-caspase-3 apoptotic pathway in vitro. These results indicate that dihydroartemisinin is a potentially valuable therapeutic agent against echinococcosis.

scholarly journals CARRAGEENAN INDUCES CELL DEATH IN RATS BLOOD

2018 ◽  
Author(s):  
O. M. Kopanytsia ◽  
M. I. Marushchak ◽  
I. Ya. Krynytska
Keyword(s):  
Caspase 3 ◽  
Chemical Properties ◽  
Annexin V ◽  
Binding Assays ◽  
Apoptotic Pathway ◽  
Effector Caspase ◽  
Apoptosis And Necrosis ◽  
Physical And Chemical ◽  
Increased Activity ◽  
And Chemical Properties

Background. Because of its physical and chemical properties, carrageenan is fairly widely used. About 70 % of the carrageenan produced in the world is used in the food industry. Previous studies point to the development of oxidative stress in rats, by means of which carrageenan chronic enterocolitis was modeled.Objective. The aim of our study was to investigate the level of apoptosis and necrosis in the suspension of leukocytes in rats using 0.5 % and 1.0 % solutions of carrageenan.Methods. Annexin V (V) binding assays were performed using Annexin V Apoptosis Kit (Sigma Aldrich, USA), caspase rate in leukocyte-lymphocyte blood fractions was determined by spectrofotometry.Results. It was established that in the experimental application of carrageenan, the percentage of leukocytes with signs of apoptosis in both experimental groups statistically significantly increased. It was detected by the increased activity of effector caspase-3 in 1 month after the experiment in 1.5 times in the 2nd group and in 2.8 times in the 3rd group vs control data that point to caspase-dependent apoptotic pathway in case of carrageenan usage in rats.Conclusions. Oral use of carrageenan in rats was accompanied by the increase in the number of leukocytes with signs of apoptosis. The animals that consumed 1.0 % solution of carrageenan had more obvious increase in the activity of caspase-3 in serum relative to a group of rats consuming 0.5 % of carrageenan, proving the increase in the severity of apoptotic processes in intestine with the increase of the dose of carrageenan. 

scholarly journals Sugammadex-Enhanced Neuronal Apoptosis following Neonatal Sevoflurane Exposure in Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Maiko Satomoto ◽  
Zhongliang Sun ◽  
Yushi U. Adachi ◽  
Koshi Makita
Keyword(s):  
Neuronal Apoptosis ◽  
Caspase 3 ◽  
Neuronal Damage ◽  
Intraperitoneal Administration ◽  
Binding Agent ◽  
Learning Deficits ◽  
Neonatal Mice ◽  
Transmission Electron ◽  
Pass Through ◽  
The Brain

In rodents, neonatal sevoflurane exposure induces neonatal apoptosis in the brain and results in learning deficits. Sugammadex is a new selective neuromuscular blockade (NMB) binding agent that anesthesiologists can use to achieve immediate reversal of an NMB with few side effects. Given its molecular weight of 2178, sugammadex is thought to be unable to pass through the blood brain barrier (BBB). Volatile anesthetics can influence BBB opening and integrity. Therefore, we investigated whether the intraperitoneal administration of sugammadex could exacerbate neuronal damage following neonatal 2% sevoflurane exposure via changes in BBB integrity. Cleaved caspase-3 immunoblotting was used to detect apoptosis, and the ultrastructure of the BBB was examined by transmission electron microscopy. Exposure to 2% sevoflurane for 6 h resulted in BBB ultrastructural abnormalities in the hippocampus of neonatal mice. Sugammadex alone without sevoflurane did not induce apoptosis. The coadministration of sugammadex with sevoflurane to neonatal mice caused a significant increase (150%) in neuroapoptosis in the brain compared with 2% sevoflurane. In neonatal anesthesia, sugammadex could influence neurotoxicity together with sevoflurane. Exposure to 2% sevoflurane for 6 h resulted in BBB ultrastructural abnormalities in the hippocampus of neonatal mice.

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