Role of Nrf2 in MALAT1/ HIF-1α loop on the regulation of angiogenesis in diabetic foot ulcer

Jayasuriya, Ravichandran; Umapathy, Dhamodharan; Karan, Amin; Anandharaj, Arunkumar; Kesavan, Rajesh; Ramkumar, Kunka Mohanram

doi:10.1016/j.freeradbiomed.2020.05.018

Cited by 43 publications

(30 citation statements)

References 66 publications

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“…Our laboratory has provided evidence on the dysregulation of NRF2 in T2DM patients [ 30 ]. In addition, we have demonstrated the pivotal role of NRF2 in modulating MALAT1/HIF-1α loop essential for angiogenesis [ 31 ]. Similarly, Florczyk et al have reported that the silencing of NRF2 attenuates its angiogenic potential [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Multiple Histone Deacetylases (HDAC) and Its Correlation with NRF2-Mediated Redox Regulation in the Pathogenesis of Diabetic Foot Ulcers

et al. 2020

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Nuclear factor erythroid-2-related factor 2 (Nrf2) is a protein of the leucine zipper family, which mitigates inflammation and employs cytoprotective effects. Attempting to unravel the epigenetic regulation of type 2 diabetes mellitus (T2DM) and diabetic foot ulcer (DFU), we profiled the expression of eleven isoform-specific histone deacetylases (HDACs) and correlated them with NRF2 and cytokines. This study recruited a total of 60 subjects and categorized into DFU patients (n = 20), T2DM patients (n = 20), and healthy controls (n = 20). The DFU patients were subcategorized into uninfected and infected DFU (n = 10 each). We observed a progressive decline in the expression of NRF2 and its downstream targets among T2DM and DFU subjects. The inflammatory markers IL-6 and TNF-α were significantly upregulated, whereas anti-inflammatory marker IL-10 was significantly downregulated in DFU. Of note, a significant upregulation of HDAC1, 3, 4, 11, SIRT3 and downregulation of HDAC2,8, SIRT1, SIRT2, SIRT3, SIRT7 among DFU patients were observed. The significant positive correlation between NRF2 and SIRT1 in DFU patients suggested the vital role of NRF2/SIRT1 in redox homeostasis and angiogenesis. In contrast, the significant negative correlation between NRF2 and HDAC1, 3 and 4, implied an imbalance in NRF2-HDAC1, 3, 4 circuit. Furthermore, a significant positive correlation was observed between HDAC4 and IL-6, and the negative correlation between SIRT1 and IL-6 suggested the pro-inflammatory role of HDAC4 and the anti-inflammatory role of SIRT1 in NRF2 signaling. In conclusion, the epigenetic changes such as upregulation of HDAC1, 3, 4, 11, SIRT3 and downregulation of HDAC2, 8, SIRT1, SIRT2, SIRT6, SIRT7 and their association with NRF2 as well as inflammatory markers are suggestive of their roles in pathophysiology of T2DM and DFU.

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Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Multiple Histone Deacetylases (HDAC) and Its Correlation with NRF2-Mediated Redox Regulation in the Pathogenesis of Diabetic Foot Ulcers

et al. 2020

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“…Previous studies have validated lncRNA-TF interactions, for example, MALAT1 and NF-κB (Ding et al, 2018), TUG1 and PPARG in mesangial cells of DN (Duan et al, 2017), upregulated PVT1 and the JNK/NF-κB signaling pathways. In diabetic foot, MALAT and NEF2L2 forms a loop regulation of angiogenesis with MALAT1/HIF1A (Jayasuriya et al, 2020). NEAT1 suppresses miR-124 and NF-κB pathway.…”

Section: Discussionmentioning

confidence: 99%

Identification of Cooperative Gene Regulation Among Transcription Factors, LncRNAs, and MicroRNAs in Diabetic Nephropathy Progression

Chen

Wang

et al. 2020

Front. Genet.

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The pathogenesis of diabetic nephropathy (DN) is accompanied by alterations in biological function and signaling pathways regulated through complex molecular mechanisms. A number of regulatory factors, including transcription factors (TFs) and non-coding RNAs (ncRNAs, including lncRNAs and miRNAs), have been implicated in DN; however, it is unclear how the interactions among these regulatory factors contribute to the development of DN pathogenesis. In this study, we developed a network-based analysis to decipher interplays between TFs and ncRNAs regulating progression of DN by combining omics data with regulatory factor-target information. To accomplish this, we identified differential expression programs of mRNAs and miRNAs during early DN (EDN) and established DN. We then uncovered putative interactive connections among miRNA-mRNA, lncRNA-miRNA, and lncRNA-mRNA implicated in transcriptional control. This led to the identification of two lncRNAs (MALAT1 and NEAT1) and the three TFs (NF-κB, NFE2L2, and PPARG) that likely cooperate with a set of miRNAs to modulate EDN and DN target genes. The results highlight how crosstalk among TFs, lncRNAs, and miRNAs regulate the expression of genes both transcriptionally and post-transcriptionally, and our findings provide new insights into the molecular basis and pathogenesis of progressive DN.

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“…It has been reported that Nrf2 and HIF-1a can regulate angiogenesis in DFUs by activating MALAT1/HIF-1a signaling. 109 Expression of lncRNA-MALAT1 was significantly reduced in patients with DFUs, and its reduction was positively correlated with the expression of angiogenic factors Nrf2, HIF-1a, and VEGF. Similar results were observed after knocking out lncRNA-MALAT1.…”

Section: Regulation Of Ecm Remodelingmentioning

confidence: 91%

The progress, prospects, and challenges of the use of non-coding RNA for diabetic wounds

Wei

Liu

et al. 2021

Molecular Therapy - Nucleic Acids

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Chronic diabetic wounds affect the quality of life of patients, resulting in significant social and economic burdens on both individuals and the health care system. Although treatment methods for chronic diabetic wounds have been explored, there remains a lack of effective treatment strategies; therefore, alternative strategies must be explored. Recently, the abnormal expression of non-coding RNA in diabetic wounds has received widespread attention since it is an important factor in the development of diabetic wounds. This article reviews the regulatory role of three common non-coding RNAs (microRNA [miRNA], long non-coding RNA [lncRNA], and circular RNA [circRNA]) in diabetic wounds and discusses the diagnosis, treatment potential, and challenges of non-coding RNA in diabetic wounds. This article provides insights into new strategies for diabetic wound diagnosis and treatment at the genetic and molecular levels. ncRNA ncRNA refers to a type of RNA that does not encode protein. In the past, it has been shown to participate in a variety of biological processes and play important transcriptional and post-transcriptional regulatory functions. 18 ncRNAs are divided into two categories based on the length of the RNA chain; lncRNA have lengths greater than 200 nucleotides, and small ncRNAs (snRNA) have lengths less than 200 nucleotides. snRNAs can be subdivided into miRNAs and circRNAs. 19 miRNAs inhibit the expression of target genes by binding to the 3 0 untranslated region (3 0 UTR) of the target mRNA. 20 The miRNA gene is processed and cleaved by RNA polymerase II (Pol II) enzyme and endonuclease Drosha III to produce pre-miRNA, which is

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Role of Nrf2 in MALAT1/ HIF-1α loop on the regulation of angiogenesis in diabetic foot ulcer

Cited by 43 publications

References 66 publications

Gene Expression Profiling of Multiple Histone Deacetylases (HDAC) and Its Correlation with NRF2-Mediated Redox Regulation in the Pathogenesis of Diabetic Foot Ulcers

Gene Expression Profiling of Multiple Histone Deacetylases (HDAC) and Its Correlation with NRF2-Mediated Redox Regulation in the Pathogenesis of Diabetic Foot Ulcers

Identification of Cooperative Gene Regulation Among Transcription Factors, LncRNAs, and MicroRNAs in Diabetic Nephropathy Progression

The progress, prospects, and challenges of the use of non-coding RNA for diabetic wounds

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