ABSTRACT
Background: Diabetic nephropathy (DN) which refers to the cases with biopsy proven kidney lesions, is one of the main complications of diabetes all around the world; however, the underlying biological changes causing DN remain to be understood. Studying the alterations in gene expression profiles could give a holistic view of the molecular pathogenicity of DN and aid to discover key molecules as potential therapeutic targets. Here, we performed a meta-analysis study that included microarray gene expression profiles coming from glomerular samples of DN patients in order to acquire a list of consensus Differentially Expressed Genes (meta-DEGs) correlated with DN. Methods: After quality control and normalization steps, five gene expression datasets (GES1009, GSE30528, GSE47183, GSE104948, and GSE93804) were entered into the meta-analysis. The meta-analysis was performed by random effect size method and the meta-DEGs were put through network analysis and different pathway enrichment analyses steps. MiRTarBase and TRRUST databases were utilized to predict the meta-DEGs related miRNAs and transcription factors. A co-regulatory network including DEGs, transcription factors and miRNAs was constructed by Cytoscape, and top molecules were identified based on centrality scores in the network.(AU)
Antecedentes: La nefropatía diabética (ND), que se refiere a los casos con lesiones renales comprobadas por biopsia, es una de las principales complicaciones de la diabetes en todo el mundo. Sin embargo, los cambios biológicos subyacentes que causan la ND aún no se han entendido. Aquí realizamos un estudio de metaanálisis que incluyó perfiles de expresión génica de micromatrices provenientes de muestras glomerulares de pacientes con ND para adquirir una lista de genes expresados diferencialmente (meta-DEG) de consenso correlacionados con ND. Métodos: Después de los pasos de control de calidad y normalización, se ingresaron en el metaanálisis cinco conjuntos de datos de expresión génica (GES1009, GSE30528, GSE47183, GSE104948 y GSE93804). El metaanálisis se realizó mediante el método de tamaño de efecto aleatorio y los meta-DEG se sometieron a análisis de red y a diferentes pasos de análisis de enriquecimiento de ruta. Se utilizaron las bases de datos MiRTarBase y TRRUST para predecir los factores de transcripción y los miARN relacionados con los meta-DEG. Cytoscape construyó una red de corregulación que incluye DEG, factores de transcripción y miARN, y las moléculas principales se identificaron en función de las puntuaciones de centralidad en la red. (AU)
Subject(s)
Humans , Diabetic Nephropathies/genetics , Transcriptome , Transcription Factors , Systems BiologyABSTRACT
BACKGROUND: Diabetic nephropathy (DN) which refers to the cases with biopsy proven kidney lesions, is one of the main complications of diabetes all around the world; however, the underlying biological changes causing DN remain to be understood. Studying the alterations in gene expression profiles could give a holistic view of the molecular pathogenicity of DN and aid to discover key molecules as potential therapeutic targets. Here, we performed a meta-analysis study that included microarray gene expression profiles coming from glomerular samples of DN patients in order to acquire a list of consensus Differentially Expressed Genes (meta-DEGs) correlated with DN. METHODS: After quality control and normalization steps, five gene expression datasets (GES1009, GSE30528, GSE47183, GSE104948, and GSE93804) were entered into the meta-analysis. The meta-analysis was performed by random effect size method and the meta-DEGs were put through network analysis and different pathway enrichment analyses steps. MiRTarBase and TRRUST databases were utilized to predict the meta-DEGs related miRNAs and transcription factors. A co-regulatory network including DEGs, transcription factors and miRNAs was constructed by Cytoscape, and top molecules were identified based on centrality scores in the network. RESULTS: The identified meta-DEGs were 1364 DEGs including 665 downregulated and 669 upregulated DEGs. The results of pathway enrichment analysis showed, "immune system", "extracellular matrix organization", "hemostasis", "signal transduction", and "platelet activation" to be the top enriched terms with involvement of the meta-DEGs. After construction of the multilayer regulatory network, several top DEGs (TP53, MYC, BTG2, VEGFA, PTEN, etc.), as well as top miRNAs (miR-335, miR-16, miR-17, miR-20a, and miR-93), and transcription factors (SP1, STAT3, NF-KB1, RELA, E2F1), were introduced as potential therapeutic targets in DN. Among the regulatory molecules, miR-335-5p and SP1 were the most interactive miRNA and transcription factor molecules with the highest degree scores in the constructed network. CONCLUSION: By performing a meta-analysis of available DN-related transcriptomics datasets, we reached a consensus list of DEGs for this complicated disorder. Further enrichment and network analyses steps revealed the involved pathways in the DN pathogenesis and marked the most potential therapeutic targets in this disease.
Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Immediate-Early Proteins , MicroRNAs , Humans , Diabetic Nephropathies/metabolism , Gene Expression Profiling/methods , MicroRNAs/genetics , Transcriptome , Transcription Factors/genetics , Transcription Factors/metabolism , Immediate-Early Proteins/genetics , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Context: Diabetes is one of the most common causes of neuropathy. Morbidity and mortality increase in patients suffering from diabetic polyneuropathy and are experienced by approximately 10 to 54% of diabetic patients. Severe pain, loss of sensation, increased risk of ulceration, and even amputation are the complications of diabetic neuropathy. Intradermal injection of botulinum toxin type-A (BTX-A) is a relatively novel method for the treatment of painful diabetic neuropathy. This method is becoming popular considering its acceptable and long-lasting pain control and minimal systemic side effects. Methods: This narrative systematic review aimed to evaluate the effectiveness of intradermal BTX-A injection on painful diabetic neuropathy. The queried databases included PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Web of Science, Scopus, and Google Scholar. The final search was performed in February 2022, and no time limits were set for the search. All the relevant clinical trials were included. The inclusion criteria and search strategy were set as follows: Type of study: Randomized clinical trial (RCT) or other types of interventional studies; publication date: All published studies until February 22, 2022; sample size: No restrictions; outcomes: Effect on diabetic neuropathy pain; quality: Earning a minimum acceptable score based on critical appraisal; and language: English. The searches and article screening were performed by two independent reviewers to minimize the possibility of bias. In case of disagreement about a study, the comments of an expert (as a third person) were used to resolve the ambiguity. Results: In a review of 4 RCTs and 1 case-control study on the effectiveness of BTX-A in reducing the pain of diabetic neuropathy, 273 patients were evaluated in total. The lowest and highest number of subjects was 18 and 141. The sex distribution included 43.22% men and 56.77% women, all of whom were 47.8 to 74.8 years old. Three studies were conducted in Iran, Taiwan, and Egypt. The results of this review showed significant improvement in pain reduction, e.g., based on the Visual Analog Scale (VAS) and Neuropathic Pain Scale (NPS). A few studies evaluated sleep and psychosocial complications, and their results indicated a statistically significant improvement in the Pittsburgh sleep quality index (PSQI) and the physical subscale of the 36-Item Short Form Survey (SF-36). Conclusions: The results of this systematic review demonstrated that intradermal injection of BTX-A causes significant and long-term (up to 12 weeks) improvement in diabetic neuropathy pain. The improvement in sleep and mental or physical functions was not consistent, and no conclusive result could be reached.
