High glucose-induced PRDX3 acetylation contributes to glucotoxicity in pancreatic β-cells: Prevention by Teneligliptin

Elumalai, Suma; Karunakaran, Udayakumar; Moon, Jun Sung; Won, Kyu Chang

doi:10.1016/j.freeradbiomed.2020.07.030

Cited by 34 publications

(33 citation statements)

References 51 publications

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“…Our findings demonstrate that oxidative stress and pyroptosis are not independent but rather interact to facilitate the complexity of APAP-induced liver injury, which is partly consistent with the view of Diao (51). PRX3 plays a major role in mitochondrial redox signaling (25) and is a crucial factor in various diseases, such as colon cancer, chronic hyperglycemia and hepatocellular carcinoma (52)(53)(54). In the present study, for the first time, we demonstrated that PRX3 overexpression mitigates APAP-induced liver pyroptosis, although this alleviation may occur through other pathological processes, which needs to be further investigated.…”

Section: Discussionsupporting

confidence: 87%

Peroxiredoxin 3 Inhibits Acetaminophen-Induced Liver Pyroptosis Through the Regulation of Mitochondrial ROS

et al. 2021

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Pyroptosis is a newly discovered form of cell death. Peroxiredoxin 3 (PRX3) plays a crucial role in scavenging reactive oxygen species (ROS), but its hepatoprotective capacity in acetaminophen (APAP)-induced liver disease remains unclear. The aim of this study was to assess the role of PRX3 in the regulation of pyroptosis during APAP-mediated hepatotoxicity. We demonstrated that pyroptosis occurs in APAP-induced liver injury accompanied by intense oxidative stress and inflammation, and liver specific PRX3 silencing aggravated the initiation of pyroptosis and liver injury after APAP intervention. Notably, excessive mitochondrial ROS (mtROS) was observed to trigger pyroptosis by activating the NLRP3 inflammasome, which was ameliorated by Mito-TEMPO treatment, indicating that the anti-pyroptotic role of PRX3 relies on its powerful ability to regulate mtROS. Overall, PRX3 regulates NLRP3-dependent pyroptosis in APAP-induced liver injury by targeting mitochondrial oxidative stress.

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Section: Discussionsupporting

confidence: 87%

Peroxiredoxin 3 Inhibits Acetaminophen-Induced Liver Pyroptosis Through the Regulation of Mitochondrial ROS

et al. 2021

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“…Numerous experiments have shown that certain proteins will undergo acetylation modification when stimulated by high glucose. The influence of glucotoxicity on the acetylation level of intracellular proteins in key cells, including pancreatic β cells, hepatocytes, neural stem cells, and osteoclasts, is closely linked to cell function and even the occurrence and development of diseases ( Zhang et al, 2019 ; Zhou et al, 2019 ; Elumalai et al, 2020 ; Guo et al, 2021 ). Furthermore, the acetylation of DNA/RNA binding transcription factor Yin Yang 1 (YY1) in renal tubular epithelial cells under high glucose conditions has been shown to increase epithelial-mesenchymal transition (EMT) ( Du et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

Wan

Jiang

et al. 2021

Front. Genet.

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Diabetic nephropathy is considered one of the most common microvascular complications of diabetes and the pathophysiology involves multiple factors. Progressive diabetic nephropathy is believed to be related to the structure and function of the tubular epithelial cells in the kidney. However, the role of lysine acetylation in lesions of the renal tubular epithelial cells arising from hyperglycemia is poorly understood. Consequently, in this study, we cultured mouse renal tubular epithelial cells in vitro under high glucose conditions and analyzed the acetylation levels of proteins by liquid chromatography-high-resolution mass spectrometry. We identified 48 upregulated proteins and downregulated 86 proteins. In addition, we identified 113 sites with higher acetylation levels and 374 sites with lower acetylation levels. Subcellular localization analysis showed that the majority of the acetylated proteins were located in the mitochondria (43.17%), nucleus (28.57%) and cytoplasm (16.19%). Enrichment analysis indicated that these acetylated proteins are primarily associated with oxidative phosphorylation, the citrate cycle (TCA cycle), metabolic pathways and carbon metabolism. In addition, we used the MCODE plug-in and the cytoHubba plug-in in Cytoscape software to analyze the PPI network and displayed the first four most compact MOCDEs and the top 10 hub genes from the differentially expressed proteins between global and acetylated proteomes. Finally, we extracted 37 conserved motifs from 4915 acetylated peptides. Collectively, this comprehensive analysis of the proteome reveals novel insights into the role of lysine acetylation in tubular epithelial cells and may make a valuable contribution towards the identification of the pathological mechanisms of diabetic nephropathy.

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“…To validate key findings from the proteomic analysis, immunofluorescence staining of pancreatic tissue sections was performed using a separate cohort of NOD mice aged 9 to 13 weeks and at diabetes onset. Three protein targets, PDIA1, 14-3-3b, and PRDX3, were selected for validation experiments based on top hits from the analysis shown in Figure 2B and their known roles in maintaining β cell function (30,31,40,41). Consistent with proteomics data, the staining intensity of islet PDIA1 ( Figure 6A ) and 14-3-3b increased from 9-13 weeks in NOD mice, followed by a significant loss of target protein expression at T1D onset ( Figure 6B ).…”

Section: Resultsmentioning

confidence: 99%

A discovery-based proteomics approach identifies protein disulfide isomerase (PDIA1) as a biomarker of β cell stress in type 1 diabetes

Syed

Singhal

Raedschelders

et al. 2021

Preprint

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Background: Activation of stress pathways intrinsic to the β cell are thought to both accelerate β cell death and increase β cell immunogenicity in type 1 diabetes (T1D). However, information on the timing and scope of these responses is lacking. Methods: To identify temporal and disease-related changes in islet β cell protein expression, data independent acquisition-mass spectrometry was performed on islets collected longitudinally from NOD mice and NOD-SCID mice rendered diabetic through T cell adoptive transfer. Findings: In islets collected from female NOD mice at 10, 12, and 14 weeks of age, we found a time-restricted upregulation of proteins involved in the maintenance of β cell function and stress mitigation, followed by loss of expression of protective proteins that heralded diabetes onset. Pathway analysis identified EIF2 signaling and the unfolded protein response, mTOR signaling, mitochondrial function, and oxidative phosphorylation as commonly modulated pathways in both diabetic NOD mice and NOD-SCID mice rendered acutely diabetic by adoptive transfer, highlighting this core set of pathways in T1D pathogenesis. In immunofluorescence validation studies, β cell expression of protein disulfide isomerase A1 (PDIA1) and 14-3-3b were found to be increased during disease progression in NOD islets, while PDIA1 plasma levels were increased in pre-diabetic NOD mice and in the serum of children with recent-onset T1D compared to age and sex-matched non-diabetic controls. Interpretation: We identified a common and core set of modulated pathways across distinct mouse models of T1D and identified PDIA1 as a potential human biomarker of β cell stress in T1D.

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High glucose-induced PRDX3 acetylation contributes to glucotoxicity in pancreatic β-cells: Prevention by Teneligliptin

Cited by 34 publications

References 51 publications

Peroxiredoxin 3 Inhibits Acetaminophen-Induced Liver Pyroptosis Through the Regulation of Mitochondrial ROS

Peroxiredoxin 3 Inhibits Acetaminophen-Induced Liver Pyroptosis Through the Regulation of Mitochondrial ROS

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

A discovery-based proteomics approach identifies protein disulfide isomerase (PDIA1) as a biomarker of β cell stress in type 1 diabetes

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