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Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine.
Cell Physiol Biochem 2017; 41(2):742-754CP

Abstract

BACKGROUND/AIM

Accumulation of advanced glycation end products (AGEs) is a major cause of diabetes mellitus (DM) skin complications. Methylglyoxal (MGO), a reactive dicarbonyl compound, is a crucial intermediate of AGEs generation. N-acetyl-L-cysteine (NAC), an active ingredient of some medicines, can induce endogenous GSH and hydrogen sulfide generation, and set off a condensation reaction with MGO. However, there is rare evidence to show NAC can alleviate DM-induced skin injury through inhibition of AGEs generation or toxicity. The present study aimed to observe the effects of NAC on MGO-induced inflammatory injury and investigate the roles of AGEs and its receptor (RAGE) in NAC's dermal protection in human HaCaT keratinocytes.

METHODS

The cells were exposed to MGO to simulate a high MGO status in diabetic blood or tissues. The content of AGEs in serum or cell medium was measured with ELISA. The protective effects of NAC against MGO-induce injury were evaluated by administration before MGO one hour, in virtue of cell viability, mitochondrial membrane potential, inflammation reaction, nuclear factor (NF)-κB activation, matrix metalloproteinase (MMP)-9 expression, as well as cellular behavioral function.

RESULTS

We found the AGEs levels of patients with DM were elevated comparing with healthy volunteers. The in vitro AGEs generation was also able to be enhanced by the exposure of HaCaT cells to MGO, which reduced dose-dependently cellular viability, damaged mitochondrial function, triggered secretion of interleukin (IL)-6 and IL-8, activated NF-κB and upregulated MMP-9 expression. Furthermore, the exposure caused cellular adhesion and migration dysfunction, as well as collagen type I inhibition. Importantly, before the exposure to MGO, the preconditioning with NAC significantly attenuated MGO-induced AGEs generation, improved cellular viability and mitochondrial function, partially reversed the overexpression of proinflammatory factors and MMP-9, as well as the activation of NF-κB. Lastly, NAC blocked MGO-induced RAGE upregulation, and inhibition of RAGE with its neutralizing antibody significantly alleviated MGO-induced NF-κB activation, MMP-9 upregulation and inflammatory injury in HaCaT cells.

CONCLUSION

The present work indicates the administration of NAC can prevent MGO-induced dermal inflammatory injury through inhibition of AGEs/RAGE signal, which may provide a basal support for the treatment of diabetic skin complications with NAC-containing medicines in the future.

Authors+Show Affiliations

Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou, China Affiliated Cancer Hospital & Institute, Guangzhou, ChinaKey Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou, ChinaKey Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou, ChinaKey Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou, ChinaKey Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou, ChinaKey Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou, ChinaKey Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou, ChinaKey Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou, China Affiliated Cancer Hospital & Institute, Guangzhou, China Quality Control Section of Academic Affairs, Guangzhou Medical University, Guangzhou, China

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28214842

Citation

Yang, Chun-Tao, et al. "Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection By N-Acetyl-L-Cysteine." Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, vol. 41, no. 2, 2017, pp. 742-754.
Yang CT, Meng FH, Chen L, et al. Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine. Cell Physiol Biochem. 2017;41(2):742-754.
Yang, C. T., Meng, F. H., Chen, L., Li, X., Cen, L. J., Wen, Y. H., ... Zhang, H. (2017). Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, 41(2), pp. 742-754. doi:10.1159/000458734.
Yang CT, et al. Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection By N-Acetyl-L-Cysteine. Cell Physiol Biochem. 2017;41(2):742-754. PubMed PMID: 28214842.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine. AU - Yang,Chun-Tao, AU - Meng,Fu-Hui, AU - Chen,Li, AU - Li,Xiang, AU - Cen,Lai-Jian, AU - Wen,Yu-Hua, AU - Li,Cai-Chen, AU - Zhang,Hui, Y1 - 2017/02/13/ PY - 2016/07/29/received PY - 2017/01/10/accepted PY - 2017/2/20/pubmed PY - 2017/6/7/medline PY - 2017/2/20/entrez KW - Advanced glycation end products KW - Delayed wound healing KW - Diabetes mellitus KW - Inflammation KW - Keratinocytes KW - N-acetyl-L-cysteine SP - 742 EP - 754 JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology JO - Cell. Physiol. Biochem. VL - 41 IS - 2 N2 - BACKGROUND/AIM: Accumulation of advanced glycation end products (AGEs) is a major cause of diabetes mellitus (DM) skin complications. Methylglyoxal (MGO), a reactive dicarbonyl compound, is a crucial intermediate of AGEs generation. N-acetyl-L-cysteine (NAC), an active ingredient of some medicines, can induce endogenous GSH and hydrogen sulfide generation, and set off a condensation reaction with MGO. However, there is rare evidence to show NAC can alleviate DM-induced skin injury through inhibition of AGEs generation or toxicity. The present study aimed to observe the effects of NAC on MGO-induced inflammatory injury and investigate the roles of AGEs and its receptor (RAGE) in NAC's dermal protection in human HaCaT keratinocytes. METHODS: The cells were exposed to MGO to simulate a high MGO status in diabetic blood or tissues. The content of AGEs in serum or cell medium was measured with ELISA. The protective effects of NAC against MGO-induce injury were evaluated by administration before MGO one hour, in virtue of cell viability, mitochondrial membrane potential, inflammation reaction, nuclear factor (NF)-κB activation, matrix metalloproteinase (MMP)-9 expression, as well as cellular behavioral function. RESULTS: We found the AGEs levels of patients with DM were elevated comparing with healthy volunteers. The in vitro AGEs generation was also able to be enhanced by the exposure of HaCaT cells to MGO, which reduced dose-dependently cellular viability, damaged mitochondrial function, triggered secretion of interleukin (IL)-6 and IL-8, activated NF-κB and upregulated MMP-9 expression. Furthermore, the exposure caused cellular adhesion and migration dysfunction, as well as collagen type I inhibition. Importantly, before the exposure to MGO, the preconditioning with NAC significantly attenuated MGO-induced AGEs generation, improved cellular viability and mitochondrial function, partially reversed the overexpression of proinflammatory factors and MMP-9, as well as the activation of NF-κB. Lastly, NAC blocked MGO-induced RAGE upregulation, and inhibition of RAGE with its neutralizing antibody significantly alleviated MGO-induced NF-κB activation, MMP-9 upregulation and inflammatory injury in HaCaT cells. CONCLUSION: The present work indicates the administration of NAC can prevent MGO-induced dermal inflammatory injury through inhibition of AGEs/RAGE signal, which may provide a basal support for the treatment of diabetic skin complications with NAC-containing medicines in the future. SN - 1421-9778 UR - https://www.unboundmedicine.com/medline/citation/28214842/Inhibition_of_Methylglyoxal_Induced_AGEs/RAGE_Expression_Contributes_to_Dermal_Protection_by_N_Acetyl_L_Cysteine_ L2 - https://www.karger.com?DOI=10.1159/000458734 DB - PRIME DP - Unbound Medicine ER -