Combined analysis of circRNA and mRNA profiles and interactions in patients with Diabetic Foot and Diabetes Mellitus

Abstract

In order to elucidate the pathogenesis and explore new biomarkers for diabetes and diabetic foot (DF), an analysis using RNA sequencing affords broader insights into gene expression regulatory networks in DF. To better explore the molecular basis of DF, we carried out an analysis of circular RNA (circRNA) and messenger RNA (mRNA) expression profiles of serum samples from DF patients and diabetes mellitus (DM) patients. The potential roles and interactions of differentially expressed circRNAs and mRNAs were classified by gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Compared with diabetes patients, 279 mRNAs were upregulated and 353 mRNAs were downregulated in the serum of DF patients, and 33 circRNAs were differently expressed. The differential genes at the nodes of the interaction network were screened, and TLR6 RUNX1 and ST2 were found to be related to the progression of diabetes and DF. The enrichment pathway analysis revealed that the lysosomal pathway played a critical role in the occurrence and development of DF. TLR6, RUNX1, and ST2 mRNA expressions and the lysosomal pathway may be involved in the pathogenesis of diabetes and DF. In addition, methane metabolism and Chagas disease pathways were observed in the occurrence and development of DF, which is a new discovery in this study. This study provides clues on the molecular mechanisms of DF at the circRNA and mRNA levels.

Diabetic Wound-Healing Science

“…A number of serum biomarkers have been identified, including albumin [ 257 ], PLR and NLR [ 122 , 258 ], angiopoietin-like 2 (ANGPTL2) [ 259 ], lipoprotein-associated phospholipase A2 and interleukin-18 (IL-18) [ 260 ], pentraxin 3 [ 261 ], T-cell differentiation markers [ 262 ], stem/progenitor cells [ 263 ], as well as neutrophil extracellular traps (NETs)-specific markers [ 264 ]. Recent genomic analyses of DFU have utilized circRNAs [ 265 , 266 , 267 ], lncRNAs [ 268 ], miRNAs [ 99 , 100 , 269 ], genetic polymorphisms [ 270 , 271 , 272 ], cytokine arrays [ 273 ], and network maps [ 274 ] for the identification of other potential biomarkers for DFU diagnosis and prognosis. With the advent of bioinformatic analyses predicting factors for diabetic complications [ 275 ], the integration of computational algorithms with clinical observations and biomarker results will likely become the new standard for DFU care.…”

Profile and Functional Prediction of Plasma Exosome-Derived CircRNAs From Acute Ischemic Stroke Patients

“…CircRNAs are stable and abundant and function as effective diagnostic biomarkers of stroke, like hsa_circ_0001599 (Li et al, 2021) and hsa_circ_0141720 (Chen Y. et al, 2020). In order to explore new circRNAs as potential biomarkers of AIS, ROC curves of four circRNAs (hsa_circ_0112036, hsa_circ_0066867, hsa_circ_0093708, and hsa_circ_0041685) predicted to play a role in the pathogenesis of AIS were analyzed.…”

“…A tissue-specific circRNA database showed that the major origins of differentially quantified circRNAs with tissue specificity included the digestive system, the cardiovascular system, and lungs. The diseases contributing to AIS, like hypertension, atherosclerosis, and diabetes mellitus, cause marked impairment of the cardiovascular system, disrupting the expression of circRNAs ( Wu et al, 2017 ; Zhao et al, 2020 ; Fu and Sun, 2021 ). The aberrant profile of circRNAs specific to the digestive system could be in part the result of the eating habits of patients with AIS.…”

“…Recently, circRNAs have been considered to be potential biomarkers or targets for diagnosis or treatment of acute IS (AIS) (Lu et al, 2020;Zuo et al, 2020). CircUCK2, as a miRNA sponge, markedly reduced IS infarct volume and improved neurological impairment in the mouse model of focal cerebral ischemia and reperfusion (Chen W. et al, 2020), while circHECTD1 aggravated cerebral infarction volume and neuronal apoptosis in the mouse model of IS (Dai et al, 2021). Moreover, circRNAs exhibit dynamic expression patterns in a series of physiological and pathological conditions and possess important regulatory effects.…”

Cell Therapy for Critical Limb Ischemia: Advantages, Limitations, and New Perspectives for Treatment of Patients with Critical Diabetic Vasculopathy

“…In a high throughput RNA-sequencing study, the comparison between blood samples from three just-diagnosed patients with T2D and three healthy patients unravelled a multitude of differentially expressed miRNAs, lncRNAs, circRNAs as well as mRNAs [144]. Furthermore, another RNA-sequencing study comparing patients with diabetes with and without diabetic foot complications showed that 632 mRNAs and 33 circRNAs were differently expressed in the sera of the two groups [145].…”