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Diabetic Enteropathy: From Molecule to Mechanism-Based Treatment.

ABSTRACT: The incidence of the micro- and macrovascular complications of diabetes is rising, mirroring the increase in the worldwide prevalence. Arguably, the most common microvascular complication is neuropathy, leading to deleterious changes in both the structure and function of neurons. Amongst the various neuropathies with the highest symptom burden are those associated with alterations in the enteric nervous system, referred to as diabetic enteropathy. The primary aim of this review is to provide a contemporaneous summary of pathophysiology of diabetic enteropathy thereby allowing a "molecule to mechanism" approach to treatment, which will include 4 distinct aspects. Firstly, the aim is to provide an overview of the diabetes-induced structural remodelling, biochemical dysfunction, immune-mediated alterations, and inflammatory properties of the enteric nervous system and associated structures. Secondly, the aim is to provide a synopsis of the clinical relevance of diabetic enteropathy. Thirdly, the aim is to discuss the various patient-reported outcome measures and the objective modalities for evaluating dysmotility, and finally, the aim is to outline the clinical management and different treatment options that are available. Given the burden of disease that diabetic enteropathy causes, earlier recognition is needed allowing prompt investigation and intervention, which may lead to improvements in quality of life for sufferers.

SUBMITTER: Meldgaard T

PROVIDER: S-EPMC6165592 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Diabetic Enteropathy: From Molecule to Mechanism-Based Treatment.

Meldgaard Theresa T Olesen Søren Schou SS Farmer Adam D AD Krogh Klaus K Wendel Anne Astrid AA Brock Birgitte B Drewes Asbjørn Mohr AM Brock Christina C

Journal of diabetes research 20180916

The incidence of the micro- and macrovascular complications of diabetes is rising, mirroring the increase in the worldwide prevalence. Arguably, the most common microvascular complication is neuropathy, leading to deleterious changes in both the structure and function of neurons. Amongst the various neuropathies with the highest symptom burden are those associated with alterations in the enteric nervous system, referred to as diabetic enteropathy. The primary aim of this review is to provide a c ...[more]

PMID: 30306092

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Project description:BackgroundDiabetic nephropathy (DN) is a chronic microvascular complication in patients with diabetes mellitus, which is the leading cause of end-stage renal disease. However, the role of copper-related genes (CRGs) in DN development remains unclear.Materials and methodsCRGs were acquired from the GeneCards and NCBI databases. Based on the GSE96804 and GSE111154 datasets from the GEO repository, we identified hub CRGs for DN progression by taking the intersection of differentially expressed CRGs (DECRGs) and genes in the key module from Weighted Gene Co-expression Network Analysis. The Maximal Clique Centrality algorithm was used to identify the key CRGs from hub CRGs. Transcriptional factors (TFs) and microRNAs (miRNAs) targeting hub CRGs were acquired from publicly available databases. The CIBERSORT algorithm was used to perform comparative immune cell infiltration analysis between normal and DN samples.ResultsEighty-two DECRGs were identified between normal and DN samples, as were 10 hub CRGs, namely PTGS2, DUSP1, JUN, FOS, S100A8, S100A12, NAIP, CLEC4E, CXCR1, and CXCR2. Thirty-nine TFs and 165 miRNAs potentially targeted these 10 hub CRGs. PTGS2 was identified as the key CRG and FOS as the most significant gene among all of DECRGs. RELA was identified as the hub TF interacting with PTGS2 by taking the intersection of potential TFs from the ChEA and JASPAR public databases. let-7b-5p was identified as the hub miRNA targeting PTGS2 by taking the intersection of miRNAs from the miRwalk, RNA22, RNAInter, TargetMiner, miRTarBase, and ENCORI databases. Similarly, CREB1, E2F1, and RELA were revealed as hub TFs for FOS, and miR-338-3p as the hub miRNA. Finally, compared with those in healthy samples, there are more infiltrating memory B cells, M1 macrophages, M2 macrophages, and resting mast cells and fewer infiltrating activated mast cells and neutrophils in DN samples (all p< 0.05).ConclusionThe 10 identified hub copper-related genes provide insight into the mechanisms of DN development. It is beneficial to examine and understand the interaction between hub CRGs and potential regulatory molecules in DN. This knowledge may provide a novel theoretical foundation for the development of diagnostic biomarkers and copper-related therapy targets in DN.

Project description:BackgroundDiabetic nephropathy (DN), characterized by hyperglycemia, hypertension, proteinuria, and edema, is a unique microvascular complication of diabetes. Traditional Chinese medicine (TCM) Astragalus membranaceus (AM) has been widely used for DN in China while the pharmacological mechanisms are still unclear. This work is aimed at undertaking a network pharmacology analysis to reveal the mechanism of the effects of AM in DN. Materials and Methods. In this study, chemical constituents of AM were obtained via Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), and the potential targets of AM were identified using the Therapeutic Target Database (TTD). DisGeNET and GeneCards databases were used to collect DN-related target genes. DN-AM common target protein interaction network was established by using the STRING database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out to further explore the DN mechanism and therapeutic effect of AM. The network diagrams of the active component-action target and protein-protein interaction (PPI) networks were constructed using Cytoscape software.ResultsA total of 16 active ingredients contained and 78 putative identified target genes were screened from AM, of which 42 overlapped with the targets of DN and were considered potential therapeutic targets. The analysis of the network results showed that the AM activity of component quercetin, formononetin, calycosin, 7-O-methylisomucronulatol, and quercetin have a good binding activity with top ten screened targets, such as VEGFA, TNF, IL-6, MAPK, CCL3, NOS3, PTGS2, IL-1β, JUN, and EGFR. GO and KEGG analyses revealed that these targets were associated with inflammatory response, angiogenesis, oxidative stress reaction, rheumatoid arthritis, and other biological process.ConclusionsThis study demonstrated the multicomponent, multitarget, and multichannel characteristics of AM, which provided a novel approach for further research of the mechanism of AM in the treatment of DN.

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Project description:BackgroundThis study aimed to investigate the active components, key targets, and potential molecular mechanisms Huaiqihuang (HQH) in the treatment of diabetic kidney disease (DKD) through network pharmacology, molecular docking, and in vitro experiments.MethodsThe active components and potential targets of HQH were obtained from the TCMSP and HERB databases. The potential targets of DKD were obtained from the GeneCards, OMIM, DrugBank, and TTD databases. Protein interaction relationships were obtained from the STRING database, and a protein interaction network was constructed using Cytoscape software. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis was performed using the Metascape database. Molecular docking was performed using AutoDock software to verify the binding between key compounds and core target genes. In vitro experiments were conducted using human renal proximal tubular epithelial cells and various methods, such as CCK8, RT-PCR, immunofluorescence, and western blot, to evaluate the effects of HQH on inflammatory factors, key targets, and pathways.ResultsA total of 48 active ingredients, 168 potential targets of HQH, and 1073 potential targets of DKD were obtained. A total of 118 potential targets, 438 biological processes, and 187 signal pathways were identified for the treatment of DKD. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis indicated that HQH may exert its therapeutic effects on DKD by regulating the expression of inflammatory factors through the nuclear factor kappa B (NF-κB) signaling pathway. The molecular docking results showed that β-sitosterol and baicalein had the highest binding affinity with key targets such as AKT1, IL6, TNF, PTGS2, IL1B, and CASP3, suggesting that they may be the most effective active ingredients of HQH in the treatment of DKD. In vitro experimental results demonstrated that HQH could enhance the viability of human renal proximal tubular epithelial cells inhibited by high glucose, decrease the levels of AKT1, TNF, IL6, PTGS2, IL1B, and CASP3, reduce the expression of NF-κB-P65 (P < .01), inhibit NF-κB-p65 nuclear translocation, and decrease chemokine expression (P < .01).ConclusionHQH may exert its therapeutic effects on DKD by inhibiting the NF-κB signaling pathway, reducing the level of pro-inflammatory cytokines, and alleviating the high glucose-induced injury of renal tubular epithelial cells.

Project description:BackgroundXuebifang (XBF), a potent Chinese herbal formula, has been employed in managing diabetic peripheral neuropathy (DPN). Nevertheless, the precise mechanism of its action remains enigmatic.PurposeThe primary objective of this investigation is to employ a bioinformatics-driven approach combined with network pharmacology to comprehensively explore the therapeutic mechanism of XBF in the context of DPN.Study design and methodsThe active chemicals and their respective targets of XBF were sourced from the TCMSP and BATMAN databases. Differentially expressed genes (DEGs) related to DPN were obtained from the GEO database. The targets associated with DPN were compiled from the OMIM, GeneCards, and DrugBank databases. The analysis of GO, KEGG pathway enrichment, as well as immuno-infiltration analysis, was conducted using the R language. The investigation focused on the distribution of therapeutic targets of XBF within human organs or cells. Subsequently, molecular docking was employed to evaluate the interactions between potential targets and active compounds of XBF concerning the treatment of DPN.ResultsThe study successfully identified a total of 122 active compounds and 272 targets associated with XBF. 5 core targets of XBF for DPN were discovered by building PPI network. According to GO and KEGG pathway enrichment analysis, the mechanisms of XBF for DPN could be related to inflammation, immune regulation, and pivotal signalling pathways such as the TNF, TLR, CLR, and NOD-like receptor signalling pathways. These findings were further supported by immune infiltration analysis and localization of immune organs and cells. Moreover, the molecular docking simulations demonstrated a strong binding affinity between the active chemicals and the carefully selected targets.ConclusionIn summary, this study proposes a novel treatment model for XBF in DPN, and it also offers a new perspective for exploring the principles of traditional Chinese medicine (TCM) in the clinical management of DPN.

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Diabetic Enteropathy: From Molecule to Mechanism-Based Treatment.

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Diabetic Enteropathy: From Molecule to Mechanism-Based Treatment.

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