Thioredoxin-mimetic peptides (TXM) inhibit inflammatory pathways associated with high-glucose and oxidative stress

Lejnev, Katia; Khomsky, Lena; Bokvist, Krister; Mistriel-Zerbib, Shani; Naveh, Tahel; Farb, Thomas B.; Alsina‐Fernandez, Jorge; Atlas, Daphné

doi:10.1016/j.freeradbiomed.2016.09.011

Cited by 23 publications

(15 citation statements)

References 38 publications

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“…Insulin resistance is well known as the major feature and cause of type 2 diabetes. Meanwhile, this is consistent with the knowledge that mitogen-activated protein kinase/ERK signaling pathway activation is involved in hepatic insulin resistance and type 2 diabetes development [30][31][32][33] . Several diabetes-related pathways were associated with Hippo signaling 34 .…”

Section: Discussionsupporting

confidence: 91%

Key genes and co‐expression network analysis in the livers of type 2 diabetes patients

Pan

Yang

2019

J of Diabetes Invest

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Aims/Introduction The incidence of type 2 diabetes is increasing worldwide. Hepatic insulin resistance and liver lipid accumulation contributes to type 2 diabetes development. The aim of the present study was to investigate the key gene pathways and co‐expression networks in the livers of type 2 diabetes patients. Materials and Methods Dataset GSE 15653 containing nine healthy individuals and nine type 2 diabetes patients was downloaded from the National Center for Biotechnology Information Gene Expression Omnibus database. Differentially expressed genes were obtained from the livers of type 2 diabetes patients, annotated pathway enrichment and protein–protein interaction network analysis. Next, functional modules and transcription factor networks were constructed. Gene co‐expression networks were analyzed by weighted correlation network analysis to identify key modules related to clinical traits, and the candidate key genes were validated in hepatic insulin resistance models in vitro . Results A total of 778 differentially expressed genes were filtered in the livers of type 2 diabetes patients, pathway enrichment analysis identified ke y pathways, such as the mitogen‐activated protein kinase signaling pathway, Hippo signaling pathway and hypoxia‐inducible factor ‐1 signaling pathway, that were associated with type 2 diabetes. Several transcription factors of three functional modules identified from protein–protein interaction networks are likely to be implicated in type 2 diabetes. Furthermore, weighted correlation network analysis identified five modules that were shown to be highly correlated with type 2 diabetes and other clinical traits. Functional annotation showed that these modules were mainly enriched in pathways such as metabolic pathways, phosphoinositide 3‐kinase‐protein kinase B signaling pathway and natural killer cell‐mediated cytotoxicity. UBE 2M and GPER were upregulated in L02 and HepG2 models, whereas P2 RY 11 only upregulated in L02 model, and UBE 2N only downregulated in HepG2 model at a significant level. Conclusions These results would offer new insights into hepatic insulin resistance, type 2 diabetes pathogenesis, development and drug discovery.

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Section: Discussionsupporting

confidence: 91%

Key genes and co‐expression network analysis in the livers of type 2 diabetes patients

Pan

Yang

2019

J of Diabetes Invest

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“…In addition, our data showed that GPR21 inhibition decreased ERK phosphorylation. ERK belongs to the mitogen-activated protein kinase family and its activity is increased in several tissues of diabetic mice [ 41 , 42 , 43 ] and in primary cells from Type 2 diabetic patients [ 44 ]. Interestingly, it is recognised that the activation of this MAPKs negatively affects insulin signalling [ 20 , 22 , 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

GPR21 Inhibition Increases Glucose-Uptake in HepG2 Cells

Kinsella

Cannito

Bordano

et al. 2021

IJMS

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GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is not fully understood. As the liver is both a major target of insulin signalling and critically involved in glucose metabolism, the aim of this study was to examine the role of GPR21 in the regulation of glucose uptake and production in human hepatocytes. In particular, HepG2 cells, which express GPR21, were adopted as cellular models. Compared with untreated cells, a significant increase in glucose uptake was measured in cells treated with siRNA to downregulate GPR21 expression or with the GPR21-inverse agonist, GRA2. Consistently, a significantly higher membrane translocation of GLUT-2 was measured under these conditions. These effects were accompanied by an increased ratio of phAKT(Ser473)/tot-AKT and phGSK-3β(Ser9)/tot-GSK-3β, thus indicating a marked activation of the insulin signalling pathway. Moreover, a significant reduction in ERK activation was observed with GPR21 inhibition. Collectively, these results indicate that GPR21 mediates the negative effects on glucose uptake by the liver cells. In addition, they suggest that the pharmacological inhibition of GPR21 could be a novel strategy to improve glucose homeostasis and counteract hepatic insulin resistance.

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“…In insulin resistance, there is usually a chronic inflammatory response, which makes the MAPK pathway play an important role in accompanying the inflammatory response of type 2 diabetes, such as diabetic nephropathy and liver lesions. However, the functional role of MAPKs in insulin resistance has not been clarified; the specific mechanism of the MAPK pathway in type 2 diabetes needs to be further studied [17][18][19][20][21].…”

Section: Discussionmentioning

confidence: 99%

Weighted Gene Coexpression Network Analysis Identified MicroRNA Coexpression Modules and Related Pathways in Type 2 Diabetes Mellitus

Feng

Zheng

et al. 2019

Oxidative Medicine and Cellular Longevity

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Objective. Type 2 diabetes mellitus (T2DM) is a metabolic disease with high incidence, which has seriously affected human life and health. MicroRNA, a short-chain noncoding RNA, plays an important role in T2DM. Identification of meaningful microRNA modules and the role of microRNAs provide a basis for searching potential biomarkers of T2DM. Materials and Methods. In this study, three newly diagnosed patients with T2DM and three controls were selected for Whole Peripheral Blood RNA Sequencing to establish a microRNA library. Weighted gene coexpression network analysis (WGCNA) was applied to construct coexpression modules and to detect the trait-related microRNA modules; then, KEGG enrichment analysis was performed to predict the biological function of the interest modules, and candidate hub microRNAs were screened out by the value of module membership (MM) and protein-protein interaction (PPI) network. Result. Four microRNA modules (blue, brown, magenta, and turquoise) were highly associated with the T2DM; the number of miRNAs in these modules ranged from 41 to 469. The Fc gamma R-mediated phagocytosis pathway, Rap1 signaling pathway, MAPK signaling pathway, and Lysosome pathway were common pathways in three of the four modules. RPS27A, UBC, and RAC1 were the top three proteins in our study; their corresponding RNAs were miR-1271-5p, miR-130a-3p, miR-130b-3p, and miR-574-3p. Conclusion. In summary, this study identified blood miRNAs in human T2DM using RNA sequencing. The findings may be the foundation for understanding the potential role of miRNAs in T2DM.

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Thioredoxin-mimetic peptides (TXM) inhibit inflammatory pathways associated with high-glucose and oxidative stress

Cited by 23 publications

References 38 publications

Key genes and co‐expression network analysis in the livers of type 2 diabetes patients

Key genes and co‐expression network analysis in the livers of type 2 diabetes patients

GPR21 Inhibition Increases Glucose-Uptake in HepG2 Cells

Weighted Gene Coexpression Network Analysis Identified MicroRNA Coexpression Modules and Related Pathways in Type 2 Diabetes Mellitus

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