Advanced Glycation End Products Induce Human Corneal Epithelial Cells Apoptosis through Generation of Reactive Oxygen Species and Activation of JNK and p38 MAPK Pathways

Shi, Long; Yu, Xiaoming; Yang, Hongling; Wu, Xinyi

doi:10.1371/journal.pone.0066781

Cited by 84 publications

(60 citation statements)

References 55 publications

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“…These concentrations of AGE-BSA are within the range used in many other studies (e.g. Nah et al (2007), Shen et al (2010), Okazaki et al (2012) and Shi et al (2013)). …”

Section: Resultssupporting

confidence: 64%

“…The apoptosis of various cell types caused by AGEs involves the activation of the p38 MAPK pathway (Shen et al 2010, Shi et al 2013), and we found that this pathway also participates in AGE-BSA-induced BMSC apoptosis. It is probably not the only MAPK pathway involved, since we were unable to completely abrogate the apoptosis of BMSCs with the p38 inhibitor.…”

Section: Discussionmentioning

confidence: 67%

“…The apoptosis of various cell types caused by AGEs involves the activation of the p38 MAPK pathway (Shen et al 2010, Shi et al 2013; thus, we sought to test the involvement of this pathway in the apoptosis of BMSCs. (Fig.…”

Section: Resultsmentioning

confidence: 99%

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AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFα production and oxidative stress

Weinberg¹,

Maymon²,

Weinreb³

2013

Journal of Molecular Endocrinology

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Diabetic humans and animals exhibit lower bone mass and healing, resulting from diminished bone formation. We have recently reported that type 1 diabetic rats have fewer bone marrow osteoprogenitor cells, and since the formation of advanced glycation end products (AGEs) in bone increases in diabetes, we explored possible mechanisms involved in AGE-induced apoptosis of rat bone marrow stromal cells (BMSCs). BMSCs isolated from 4-month-old rats were exposed to 10-400 mg/ml AGE-BSA for 16 h and apoptosis was quantified with PI/annexin V staining and flow cytometry. Signaling mechanisms were evaluated by preincubating the cells with appropriate inhibitors. The formation of reactive oxygen species (ROS) was quantified by flow cytometric analysis of DCFDA fluorescence and the expression of genes by RT-PCR analysis. AGE-BSA at a concentration of 400 mg/ml increased the apoptosis of BMSCs two-to threefold, an effect completely blocked by a pan-caspase inhibitor. BSA or high concentrations of glucose had no effect. AGE-BSA-induced BMSC apoptosis was attenuated by a p38 inhibitor but not by an NF-kB inhibitor. Treatment with AGE-BSA induced the expression of several pro-apoptotic ligands and receptors, most notably tumor necrosis factor a (TNFa), TRAIL, lymphotoxin alpha, CD40, and TNFR2. Furthermore, AGE-BSA-induced apoptosis was completely blocked by pirfenidone, an inhibitor of TNFa production/secretion. Finally, AGE-BSA increased the production of ROS in BMSCs, and its apoptogenic effect was blocked by the antioxidant N-acetylcysteine (N-acetyl-L-cysteine). Thus, AGE-BSA increases the apoptosis of rat BMSCs via the activation of caspases, involving TNFa production/ secretion, p38 MAPK signaling, and oxidative stress. We propose that increased protein glycation, such as that occurring under hyperglycemia, causes the apoptosis of BMSCs, which might significantly contribute to the development of osteopenia in diabetic animals.

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“…These concentrations of AGE-BSA are within the range used in many other studies (e.g. Nah et al (2007), Shen et al (2010), Okazaki et al (2012) and Shi et al (2013)). …”

Section: Resultssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 67%

See 1 more Smart Citation

AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFα production and oxidative stress

Weinberg¹,

Maymon²,

Weinreb³

2013

Journal of Molecular Endocrinology

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show abstract

“…ROS was reported as the upstream signal molecule of p38 MAPK, directly regulating the phosphorylation of p38, and ultimately affecting biological effect. [38][39][40][41] However, some studies demonstrated contrary views. [42][43][44] The different regulation networks may cause varied biological effects in diverse cells and organisms.…”

Section: Discussionmentioning

confidence: 99%

Danshensu Inhibits β-Adrenergic Receptors-Mediated Cardiac Fibrosis by ROS/p38 MAPK Axis

Tian

et al. 2014

Biological & Pharmaceutical Bulletin

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Danshensu, the effective ingredient of the plant Salvia miltiorrhiza (Danshen), has been widely used for treatment of cardiovascular diseases. Cardiac fibrosis is an important process in pathological cardiac remodeling and leads to heart failure. We investigated the effect of Danshensu on β-adrenergic receptor (β-AR)-mediated cardiac fibrosis and the involved signaling transduction. Danshensu inhibited cardiofibroblast proliferation and collagen I synthesis induced by isoproterenol (ISO), a selective β-AR agonist. Phosphorylation of p38 mitogen-activated protein kinase (MAPK), which mediates ISO-induced cardiac fibrosis, was negatively regulated in this process. The negative regulation depended on the ISO inhibition of reactive oxygen species (ROS) production. Taken together, Danshensu may inhibit β-AR-mediated cardiac fibrosis by negative regulation of ROS-p38 MAPK signaling.Key words Danshensu; β-adrenergic receptor; cardiac fibrosis; p38 MAPK; reactive oxygen specy Cardiac fibrosis is a pivotal phenomenon in pathological cardiac remodeling and is a hallmark of heart diseases. It is characterized by excessive extracellular matrix accumulation and fibroblast deposition and eventually destroys the organ architecture and abolishes normal function.1-3) Myocardial fibrosis is a major biological determinant of fatal events in cardiac remodeling, including heart failure, severe arrhythmias and sudden cardiac death.4,5) Cardiac fibrosis can be caused by various factors, such as the chronic activation of the sympathetic nervous system, myocardial hypoxia, ischemia, senescence, inflammation and hormones. β-Adrenergic receptors (β-ARs) and their associated guanine nucleotide regulatory protein (G protein)/adenylyl cyclase signal transduction pathways, are central to the regulation of cardiac function. Continuous activation of β-ARs plays an important role in cardiac dysfunction.6-8) Cardiac function was altered in β 1 -AR transgenic mice with cardiac hypertrophy, which could be inhibited by β-AR blockers.8) Consecutive administration with isoproterenol (ISO), a β-AR agonist, caused cardiac fibrosis in rats. 9,10) p38 mitogen-activated protein kinase (p38 MAPK) and reactive oxygen species (ROS) play a critical role in cardiac * To whom correspondence should be addressed. e-mail: lizijian@bjmu.edu.cn;zhengxh@nwu.edu.cnThe authors declare no conflict of interest. # These authors contributed equally to this work.

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“…To mimic the pathological process of kidney disease induced by diabetes mellitus, the human renal tubular epithelial cell line HK-2 was exposed to AGE-BSA in vitro. The AGE-BSA concentration at 100 g/ml was utilized, because this dose was reported to represent AGEs level in the serum of diabetic patients (17). Before incubation with AGE-BSA, only a few LC3-II puncta were detected in the HK-2 cells through immunofluorescence staining (Fig.…”

Section: Autophagic Vacuoles Are Accumulated In Tecs During the Progrmentioning

confidence: 99%

Autophagy-Lysosome Pathway in Renal Tubular Epithelial Cells Is Disrupted by Advanced Glycation End Products in Diabetic Nephropathy

Liu

Shen

Chen

et al. 2015

Journal of Biological Chemistry

104

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Background:The pathophysiological importance of autophagy in renal tubules during the development of diabetic nephropathy (DN) has been implicated. Results: Autophagy was inactivated because lysosomal membrane permeabilization and lysosomal dysfunction were triggered by advanced glycation end products. Conclusion:The autophagy-lysosome pathway is disrupted in renal tubules in DN. Significance:The findings open a new field for studying the mechanisms of DN.

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Advanced Glycation End Products Induce Human Corneal Epithelial Cells Apoptosis through Generation of Reactive Oxygen Species and Activation of JNK and p38 MAPK Pathways

Cited by 84 publications

References 55 publications

AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFα production and oxidative stress

AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFα production and oxidative stress

Danshensu Inhibits β-Adrenergic Receptors-Mediated Cardiac Fibrosis by ROS/p38 MAPK Axis

Autophagy-Lysosome Pathway in Renal Tubular Epithelial Cells Is Disrupted by Advanced Glycation End Products in Diabetic Nephropathy

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