path: root/gnqa/paper1_eval/src/data/responses/diabetes/full_response/suga_resp_07.json

{
    "created_at": "2024-04-18T18:34:34.295904Z",
    "data": {
        "amplify": false,
        "answer": "MicroRNAs and long noncoding RNAs (lncRNAs) are involved in diabetes. MicroRNAs modulate post-transcriptional control of gene expression through degradation or translational repression of key messenger RNAs. They can regulate pathogenic responses such as angiogenesis, blood flow, neural cell dysfunction, tissue-specific inflammation and glucose metabolism. They also hold potential as diagnostic biomarkers and possible drug-targets for regulation of dysfunctional cell responses. LncRNAs are implicated in complications associated with diabetes, such as diabetic retinopathy and diabetic nephropathy. They can regulate cell proliferation, viability, migration, and the expression of pathological genes via post-transcriptional mechanisms.",
        "context": {
            "02a9d5a9-41a4-4d70-b828-c4bda13fa01c": [
                {
                    "document_id": "02a9d5a9-41a4-4d70-b828-c4bda13fa01c",
                    "text": "\n\nIt is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication.Targeting early features of DN, including renal extracellular matrix accumulation (ECM) and glomerular hypertrophy, can prevent disease progression.Here we show that a megacluster of nearly 40 microRNAs and their host long non-coding RNA transcript (lnc-MGC) are coordinately increased in the glomeruli of mouse models of DN, and mesangial cells treated with transforming growth factor-b1 (TGF-b1) or high glucose.Lnc-MGC is regulated by an endoplasmic reticulum (ER) stress-related transcription factor, CHOP.Cluster microRNAs and lnc-MGC are decreased in diabetic Chop À / À mice that showed protection from DN. Target genes of megacluster microRNAs have functions related to protein synthesis and ER stress.A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice.Relevance to human DN is also demonstrated.These results demonstrate the translational implications of targeting lnc-MGC for controlling DN progression."
                },
                {
                    "document_id": "02a9d5a9-41a4-4d70-b828-c4bda13fa01c",
                    "text": "\nIt is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication.Targeting early features of DN, including renal extracellular matrix accumulation (ECM) and glomerular hypertrophy, can prevent disease progression.Here we show that a megacluster of nearly 40 microRNAs and their host long non-coding RNA transcript (lnc-MGC) are coordinately increased in the glomeruli of mouse models of DN, and mesangial cells treated with transforming growth factor-b1 (TGF-b1) or high glucose.Lnc-MGC is regulated by an endoplasmic reticulum (ER) stress-related transcription factor, CHOP.Cluster microRNAs and lnc-MGC are decreased in diabetic Chop À / À mice that showed protection from DN. Target genes of megacluster microRNAs have functions related to protein synthesis and ER stress.A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice.Relevance to human DN is also demonstrated.These results demonstrate the translational implications of targeting lnc-MGC for controlling DN progression."
                }
            ],
            "18a35699-873a-4542-b35a-3a4a14edd628": [
                {
                    "document_id": "18a35699-873a-4542-b35a-3a4a14edd628",
                    "text": "\n\nPlatelets are key partaker in CVD and their involvement in the development of cardiovascular complications is strengthened in diabetes (148).Platelets play an important role in the pathophysiology of thrombosis and represent an important source of different RNA species, including pseudogenes, intronic transcripts, non-coding RNAs, and antisense transcripts (149,150).These molecules can be released by platelets through microvescicles, contributing to the horizontal transfer of molecular signals delivered through the bloodstream to specific sites of action (151).The downregulation of miR-223, miR-126, or 146a observed in diabetic and hyperglycemic patients (137,152) has been associated with increased platelet reactivity and aggregation (153,154).In line with these findings, silencing of miR-223 in mice caused a hyperreactive and hyperadhesive platelet phenotype, and was associated with calpain activation through the increased expression of beta1 integrin, kindlin-3, and factor XIII (153,155).Moreover, the modulation of the expression levels of platelet miRNAs can also be measured in plasma.In fact, plasma levels of miR-223 and miR-126 are decreased in diabetics (137,156).This leads to the upregulation of the P2Y12 receptor, as well as P-selectin, further contributing to platelet dysfunction (156).As a result of this interaction, activation level of platelets in type 2 DM is increased (149,156,157).Consistently with this, circulating miR-223 levels are independent predictors of high on-treatment platelet reactivity (158).Another interesting mechanism linking platelets and diabetes involves miR-103b, a platelet-derived biomarker proposed for the early diagnosis of type 2 DM, and the secreted frizzledrelated protein-4 (SFRP4), a potential biomarker of early β cell dysfunction and diabetes.In fact, platelet-derived miR-103b is able to downregulate SFRP4, whose expression levels are significantly increased in pancreatic islets and in the blood of patients with prediabetes or overt diabetes (159).These interesting results identify miR-103b as a novel potential marker of prediabetes and diabetes, and disclose a novel potential therapeutic target in type 2 DM."
                },
                {
                    "document_id": "18a35699-873a-4542-b35a-3a4a14edd628",
                    "text": "\n\nIn vitro and in vivo studies concerning the mechanisms that are responsible for the endothelial dysfunction in diabetes demonstrated that, in the presence of high glucose concentrations, upregulation of miR-185 reduced the expression of the glutathione peroxidase-1 (GPx-1) gene, which encodes an enzyme that is important in the prevention of oxidative stress (129); instead upregulation of miR-34a and miR-204 contributed to endothelial cell senescence by impairing SIRT-1 expression and function (130,131).In the endothelium, miR-126 exerts proangiogenic, and anti-inflammatory activities.At a functional level, it enhances VEGF and fibroblast growth factor activities, contributing to vascular integrity and angiogenesis (132,133), recruits progenitor cells through the chemokine CXCL12 (134), while it suppresses inflammation by inhibiting TNF-α, ROS, and NADPH oxidase via HMGB1 (135).Consistently, miR-126 levels are down-regulated in both myocardial tissue and plasma from type 2 diabetic patients without any known anamnestic data for CVD (136,137), and in patients with CAD (138), suggesting that it could represent a new diagnostic marker for diabetes and CVD.Other studies in endothelial colony-forming cells, as well as in progenitor endothelial cells (EPCs) exposed to high glucose, demonstrated that miR-134 and miR-130a affected cell motility and apoptosis, respectively (139,140)."
                }
            ],
            "2dc80127-89ba-47be-9e94-d90c2105be8d": [
                {
                    "document_id": "2dc80127-89ba-47be-9e94-d90c2105be8d",
                    "text": "\n\nNumerous recent reports have demonstrated abnormal expression of various miRNAs in renal, vascular and retinal cells under diabetic conditions, and in vivo models of related diabetic complications [8,[87][88][89][90][91]. Notably, the functional relevance of these miRNAs has been highlighted by the fact they target key genes associated with the progression of, or protection against, these complications.In particular, the role of miRNAs in diabetic nephropathy has been extensively studied, including in the actions of TGF-β related to fibrosis and other key renal outcomes in vitro and in vivo [8,[87][88][89][90].In diabetic retinopathy, several miRNAs have been reported to modulate the disease by targeting factors associated with angiogenesis, inflammation, and oxidant stress in RECs and in diabetic retinas [88,89].Reports have also implicated various miRNAs in the aberrant expression of genes associated with diabetic cardiomyopathy [88,91].In addition, effective in vivo targeting of miRNAs has now been demonstrated thanks to advances in nucleotide chemistry and the design of nuclease-resistant anti-miRNAs, which suggest future translational potential of miRNA-based therapies for human diabetic complications [8].Importantly, since miRNAs are stable in biological fluids such as urine and serum [8], they are being assessed in samples from various clinical cohorts as valuable biomarkers for the early detection of diabetic complications, for which there is a major unmet clinical need.It is clear that research in the field of miRNAs and diabetic complications will continue at a rapid pace."
                }
            ],
            "34184c8d-b167-4ae8-bfce-01e18d78fe41": [
                {
                    "document_id": "34184c8d-b167-4ae8-bfce-01e18d78fe41",
                    "text": "Introduction\n\nDiabetes-related complications represent one of the most important health problems worldwide with dire social and economic projections (Cooper, 2012).One of the most important medical concerns of the diabetes epidemic is diabetic nephropathy (DN).Diabetic nephropathy is regarded as a prototypical disease of gene and environmental interactions because not all diabetic subjects with traditional risk factors develop clinically evident nephropathy, indicating a role for individual susceptibility.The majority (>85%) of GWAS-identified single nucleotide polymorphisms (SNPs) are located in the non-coding regions of the genome and thus their functional implication lies in identifying the target genes, cell types, and the mode of dysregulation caused by these non-coding SNPs (Maurano et al., 2012).Recent studies indicate that complex trait-causing variants localize to cell-type-specific, functionally important gene regulatory regions where they can disrupt or create transcription factor binding sites to alter transcript levels only in disease-target cell types (Ko and Susztak, 2013;Susztak, 2014).Several elements of the immune system including cytokines and resident chemokines, macrophage recruitment, T lymphocytes, and immune complex deposition have recently been associated with DN (Navarro-González and Mora-Fernández, 2008;Gaballa and Farag, 2013).Since renal cells are also capable of synthesizing pro-inflammatory cytokines such as tumor necrotic factor-alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), therefore, these cytokines acting in a paracrine or autocrine manner may induce significant effects leading to the development and progression of several renal disorders (Matoba et al., 2010;Pruijm et al., 2012;Shankar et al., 2011).The rationale of this study involved a concerted effort of genotyping, correlation and gene expression techniques involving three pro-inflammatory cytokine genes  in the development and progression of DN as well as identification of high risk patients involving susceptibility or poor clinical outcome."
                }
            ],
            "5d2fa6b9-8412-43cb-bc86-e9bcda73a4ef": [
                {
                    "document_id": "5d2fa6b9-8412-43cb-bc86-e9bcda73a4ef",
                    "text": "They also identified enrichment in coagulation and\ncomplement pathways, signaling pathways, tissue remodeling, and antigen presentation, including PI3K-Akt, Rap1,\nToll-like, and NOD-like. Sun et al. [25] studied diabetic retinopathy and identified four stress-inducible genes Rmb3,\nCirbp, Mt1, and Mt2 which commonly exist in most retinal\ncell types. Diabetes increases the inflammatory factor gene\nexpressions in retinal microglia and stimulates the immediate early gene expressions (IEGs) in retinal astrocytes. Van Zyl et al. [30] studied glaucoma cases and identified\nthe cell types that represent gene expressions implicated in\nglaucoma."
                }
            ],
            "6011e960-6a6e-47fe-94f2-2c21c224fd25": [
                {
                    "document_id": "6011e960-6a6e-47fe-94f2-2c21c224fd25",
                    "text": "\n\nOne of the major problems facing clinical nephrology currently throughout the world is an exponential increase in patients with end-stage renal disease (ESRD), which is largely related to a high incidence of diabetic nephropathy.The latter is characterized by a multitude of metabolic and signaling events following excessive channeling of glucose, which leads to an increased synthesis of extracellular matrix (ECM) glycoproteins resulting in glomerulosclerosis, interstitial fibrosis and ultimately ESRD.With the incidence of nephropathy at pandemic levels and a high rate of ESRD, physicians around the world must treat a disproportionately large number of diabetic patients with upto-date innovative measures.In this regard, identification of genes that are crucially involved in the progression of diabetic nephropathy would enhance the discovery of new biomarkers and could also promote the development of novel therapeutic strategies.Over the last decade, we focused on the recent methodologies of high-throughput and genome-wide screening for identification of relevant genes in various animal models, which included the following: (1) single nucleotide polymorphism-based genome-wide screening; (2) the transcriptome approach, such as differential display reverse transcription polymerase chain reaction (DDRT-PCR), representational difference analysis of cDNA (cDNA-RDA)/suppressive subtractive hybridization, SAGE (serial analysis of gene expression) and DNA Microarray; and (3) the proteomic approach and 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) coupled with mass spectroscopic analysis.Several genes, such as Tim44 (translocase of inner mito-chondrial membrane-44), RSOR/MIOX (renal specific oxidoreductase/myo-inositol oxygenase), UbA52, Rap1b (Ras-related GTPase), gremlin, osteopontin, hydroxysteroid dehydrogenase-3β isotype 4 and those of the Wnt signaling pathway, were identified as differentially expressed genes in kidneys of diabetic rodents.Functional analysis of these genes and the subsequent translational research in the clinical settings would be very valuable in the prevention and treatment of diabetic nephropathy.Future trends for identification of the biomarkers and therapeutic target genes should also include genome scale DNA/histonemethylation profiling, metabolomic approaches (e.g.metabolic phenotyping by 1H spectroscopy) and lectin microarray for glycan profiling along with the development of robust data-mining strategies."
                }
            ],
            "7e809821-000d-4fff-971d-264650e3612b": [
                {
                    "document_id": "7e809821-000d-4fff-971d-264650e3612b",
                    "text": "M A N U S C R I P T A C C E P T E D\n\nIn relation to the regulation of gene expression, the role of microRNAs (miRNAs) in diabetic retinopathy has been gaining more emphasis.miRNAs are non-coding small RNAs which modulate post-transcriptional control of gene expression through degradation or translational repression of key messenger RNAs.miRNAs can be detected in serum (free, associated with proteins or within membrane-bound particles) (Weiland et al., 2012), vitreous (Ragusa et al., 2013) and aqueous (Dunmire et al., 2013).As reviewed by Mastropasqua et al., miRNAs hold considerable interest for diabetic retinopathy since they can regulate important pathogenic responses such as angiogenesis, blood flow, neural cell dysfunction, tissue-specific inflammation and glucose metabolism (Mastropasqua et al., 2014).Although based on a small patient sample, it has been reported that three separate miRNAs (miR-21, miR-181c, and miR-1179) in serum of patients with diabetic retinopathy have potential to be used as biomarkers for early detection of disease (Li et al., 2014;Qing et al., 2014).While this is still a growing research area, miRNAs hold considerable clinical potential in the diabetic retinopathy field, both as possible drug-targets for regulation of dysfunctional cell responses and as diagnostic biomarkers."
                }
            ],
            "7ebf3dcf-0e9a-44d7-bd1c-1c49004d0753": [
                {
                    "document_id": "7ebf3dcf-0e9a-44d7-bd1c-1c49004d0753",
                    "text": "Roles of lncRNAs in diabetic complications\n\nApart from being involved in major metabolic tissues during diabetes as discussed above, lncRNAs are implicated in complications associated with diabetes.Diabetic retinopathy is one of the common complications in diabetic patients, which leads to impaired or loss of vision.Altered expression of lncRNAs, namely MALAT1 [82,83] and MEG3 [84], are reported to be associated with diabetic retinopathy.In STZ-induced diabetic rats, the expression of MALAT1 is elevated in the endothelial cells of the retina and knockdown of MALAT1 ameliorates retinopathy in STZ-induced rats [82].The lncRNA, MEG3, was also found to be downregulated in the retina of STZ-induced diabetic mice and its in vitro knockdown in retinal endothelial cells was found to regulate cell proliferation, viability, and migration [84].Hyperglycemia as in diabetes causes upregulation of ANRIL levels in endothelial cells [85,86], and this elevates the levels of the PRC2 subunit, EZH2 that consequently promotes the expression of VEGF, a key promoter of angiogenesis [85].Another major complication associated with diabetes is diabetic nephropathy, and this is considered a major cause of end-stage renal disease and disability in diabetic patients [87].Recent studies show that lncRNAs play important roles in the development of diabetic nephropathy and accumulation of extracellular matrix (ECM) proteins.There is higher expression of the lncRNA, PVT1, during diabetic nephropathy, and this increase leads to increased fibrosis due to accumulation of ECM proteins in renal cells [88]; downregulation of PVT1 reduces ECM accumulation [88].LncRNA PVT1 is also a host to miR-1207-5p and this miRNA is shown to regulate the expression of fibronectin1 (FN1), plasminogen activator inhibitor-1 (PAI1), and transforming growth factor beta 1 (TGFβ1) [89].In renal tube injury during diabetes, the lncRNA, MIAT, is under-expressed, and this negatively correlates with creatinine and BUN levels in the serum of these subjects.It has been shown to regulate cell viability of proximal convoluted renal tubules [90].In diabetic nephropathic mice, the lncRNA, MGC, is increased in renal mesangial cells.Interestingly, this lncRNA harbours a cluster of approximately 40 miRNAs, and is regulated by the ER stress marker C/EBP homologous protein (CHOP) [91].In CHOP -deficient mice, there is decreased expression of the lncRNA, MGC, and the clustered miRNAs, and these mice have shown an improvement in diabetic nephropathy [91].Diabetic nephropathy is also associated with increased levels of lincRNA, Gm4419, and this exerts its action by interacting with NF-κβ.Knockdown of this lincRNA in renal mesangial cells lowers cellular proliferation and inhibits expression of NF-κβ in hyperglycemic states [92].The lncRNA, TUG1, that is upregulated in diabetic nephropathy acts as sponge for miR-377 and regulates PPAR-γ expression which further modulates the expression of FN1, collagen type IV alpha 1 chain (COL4A1), PAI1, and TGFβ1 in renal mesangial cells [93].Diabetic cardiomyopathy is a critical end-stage complication associated with diabetes.Several such cardiovascular complications and myocardial dysfunction in diabetic patients lead to heart failure [94].Differential expression analysis in cardiac tissue from normal and diabetic rats shows that the lncRNA, MALAT1, is upregulated during cardiomyopathy and knockdown of this lncRNA improves left ventricular systolic function by reducing myocardial inflammation in diabetic rats [95,96].Decreased expression of the lncRNA, H19, is also reported during diabetes [68,70], and this often results in decreased expression of the exonic miRNA, miR-675 [97,98].mir-675 directly targets the voltage-dependent anion channel 1 (VDAC1) which is involved in mitochondria-mediated apoptosis in the cardiac tissue during diabetes.H19 overexpression in diabetic rats reduces oxidative stress, apoptosis, and inflammation, and improves ventricle function [98].LncRNAs NONRATT021972 and uc.48+ are reported to be associated with diabetic neuropathic pain [99,100], and inhibition of both have been shown to alleviate such neuropathic pain by activating the P2X3 receptor.Impaired wound closure is a notable complication associated with diabetes and a recent report shows decreased levels of the lncRNA, Lethe in such impaired dorsal wounds of diabetic mice.This was demonstrated to be associated with increased ROS production, possibly through regulation of NOX2 expression [101]."
                },
                {
                    "document_id": "7ebf3dcf-0e9a-44d7-bd1c-1c49004d0753",
                    "text": "\n\nAll these suggest towards important roles of various lncRNAs in complications associated with diabetes and, therefore, assume importance to be studied in detail."
                }
            ],
            "80e1b2af-be79-4d9b-852f-46bf3e23c963": [
                {
                    "document_id": "80e1b2af-be79-4d9b-852f-46bf3e23c963",
                    "text": "\n\nAn overall important consideration in study design is that similar to RNA, noncoding RNAs are tissue and cell specific [24,[77][78][79][80][81][82].Given that it is still unknown if pathogenic changes in AMD are localized to specific ocular tissues or systemic, one must take into consideration that potential biomarkers identified in the peripheral blood as \"disease associated\" may not reflect the disease mechanism occurring in the neural retina and/or RPE."
                }
            ],
            "88dde947-5255-40e1-92d5-afde089b517b": [
                {
                    "document_id": "88dde947-5255-40e1-92d5-afde089b517b",
                    "text": "\n\nSkol et al. developed methods to study genomics and transcriptomics together to help discover genes that cause diabetic retinopathy.Genes involved in how cells respond to high blood sugar were first identified using cells grown in the lab.By comparing the activity of these genes in people with and without retinopathy the study identified genes associated with an increased risk of retinopathy in diabetes.In people with retinopathy, the activity of the folliculin gene (FLCN) increased more in response to high blood sugar.This was further verified with independent groups of people and using computer models to estimate the effect of different versions of the folliculin gene."
                }
            ],
            "d23e9456-8ee8-46e0-9870-18ff69965c28": [
                {
                    "document_id": "d23e9456-8ee8-46e0-9870-18ff69965c28",
                    "text": "miRNAs in Kidney Disease and Diabetic Nephropathy\n\nDiabetic nephropathy is a progressive kidney disease and a major debilitating complication of both type 1 and type 2  diabetes that can lead to end-stage renal disease (ESRD) and related cardiovascular disorders.Absence or lower levels of particular miRNAs in the kidney compared with other organs may permit renal specific expression of target proteins that are important for kidney functions [45].Figure 4 depicts the connection between the role of miRNAs and kidney fibrosis.Altered expression of miRNAs causes renal fibrosis by inducing EMT, EndMT, and other fibrogenic stimuli.The accumulative effects of hyperglycaemia, inflammatory cytokines, proteinuria, ageing, high blood pressure, and hypoxia result into alteration of miRNAs expression profiles.The altered miRNAs level causes the initiation of such transition program in normal kidney, finally fibrosis.Some of the miRNAs that are more abundant in the kidney compared with other organs include miR-192, miR-194, miR-204, miR-215, and miR-216.A critical role of miRNA regulation in the progression of glomerular and tubular damage and the development of proteinuria been suggested by studies in mice with podocytespecific deletion of Dicer [46].There was a rapid progression of renal disease with initial development of albuminuria followed by pathological features of glomerulosclerosis and tubulointerstitial fibrosis.It is likely that these phenotypes are due to the global loss of miRNAs because of Dicer deletion, but, given multiple miRNAs and their myriad targets, the precise pathways responsible require identification.These investigators also identified specific miRNA changes, for example, the downregulation of the miR-30 family when Dicer was deleted.Of relevance, the miR-30 family was found to target connective tissue growth factor, a profibrotic molecule that is also downstream of transforming growth factor (TGF)- [47].Thus, the targets of these miRNAs may regulate critical glomerular and podocyte functions.These findings have also been complemented by an elegant study revealing a developmental role for the miR-30 family during pronephric kidney development in Xenopus [48].Sun et al. [49] identified five miRNAs (-192, -194, -204, -215, and -216) that were highly expressed in human and mouse kidney using miRNA microarray.A recent report using new proteomic approaches to profile and identify miRNA targets demonstrated that miR-NAs repress their targets at both the mRNA and translational levels and that the effects are mostly relatively mild [50].The role of miR-192 remains controversial and highlights the complex nature of miRNA research.Kato et al. [51] observed increased renal expression of miR-192 in streptozotocin-(STZ-) induced diabetes and in the db/db mouse and demonstrated that transforming growth factor (TGF-1) upregulated miR-192 in mesangial cells (MCs).miR-192 repressed the translation of Zeb2, a transcriptional repressor that binds to the E-box in the collagen 12 (col12) gene.They proposed that miR-192 repressed Zeb2 and resulted in increased col12 expression in vitro and contributed to increased collagen deposition in vivo.These data suggest a role for miR-192 in the development of the matrix accumulation observed in DN.It is interesting that the expression of miR-192 was increased by TGF- in mouse MCs (mesangial cells), whereas, conversely, the expression of its target, Zeb2, was decreased [51].This also paralleled the increased Col1 2 and TGF- expression [51].These results suggested that the increase in TGF- in vivo in diabetic glomeruli and in vitro in MCs can induce miR-192 expression, which can target and downregulate Zeb2 thereby to increase Col1 2.This is supported by the report showing that miR-192 is upregulated in human MCs treated with high glucose [51].TGF- induced downregulation of Zeb2 (via miR-192) and Zeb1 (via potentially another miRNA) can cooperate to enhance Col1 2 expression via de-repression at E-box elements [51].In contrast to the above, other reports suggest the relationship between miR-192 and renal fibrosis may be more complicated.Krupa et al. [52] identified two miRNAs in human renal biopsies, the expression of which differed by more than twofold between progressors and nonprogressors with respect to DN, the greatest change occurring in miR-192 which was significantly lower in patients with advanced DN, correlating with tubulointerstitial fibrosis and low glomerular filtration rate.They also reported, in contrast to the Kato et al. [51] study in MCs, that TGF-1 decreased expression of miR-192 in cultured proximal tubular cells (PTCs).These investigators concluded that a decrease in miR-192 is associated with increased renal fibrosis in vivo.Interestingly, connective tissue growth factor (CTGF) treatment also resulted in fibrogenesis but caused the induction of miR-192/215 and, consequently, decreased Zeb2 and increased E-cadherin.The contrasting findings above highlight the complex nature of miRNA research.Some of the differences may relate to models and/or experimental conditions; however, one often overlooked explanation is that some effects of miRNAs and inhibitors are likely to be indirect in nature.A recent report also showed that BMP6-induced miR-192 decreases the expression of Zeb1 in breast cancer cells [53].Thus, TGF- induced increase in the expression of key miRNAs (miR-192 and miR-200 family members) might coordinately downregulate E-box repressors Zeb1 and Zeb2 to increase Col12 expression in MCs related to the pathogenesis of DN.The proximal promoter of the Col1a2 gene responds to TGF- via smads and SP1.Conversely, the downregulation of Zeb1 and Zeb2 by TGF- via miR-200 family and miR-192 can affect upstream E-box regions.Because E-boxes are present in the upstream genomic regions of the miR-200 family, miR-200 family members may themselves be regulated by Zeb1 and Zeb2 [54].It is possible that the miR-200 family upregulated by TGF- or in diabetic glomeruli under early stages of the disease can also regulate collagen expression related to diabetic kidney disease by targeting and downregulating E-box repressors.miR-192 might initiate signaling from TGF- to upregulate miR-200 family members, which subsequently could amplify the signaling by further regulating themselves through down regulation of Ebox repressors.Such events could lead to progressive renal dysfunction under pathologic conditions such as diabetes, in which TGF- levels are enhanced.Conversely, there are several reports that miR-200 family members and miR-192 can be suppressed by TGF-, and this promotes epithelial-tomesenchymal transition (EMT) in cancer and other kidneyderived epithelial cell lines via subsequent upregulation of targets Zeb1 and Zeb2 to repress E-cadherin [54,55]."
                }
            ],
            "e66846a6-1546-481b-baae-a55fc524c8af": [
                {
                    "document_id": "e66846a6-1546-481b-baae-a55fc524c8af",
                    "text": "\n\nDR. HARRINGTON: You mentioned Liu's data from China [abstract; Liu Z-H et al J Am Soc Nephrol 14:400A, 2003], which overwhelmed me.Apparently there are 182 genes whose expression is up-or down-regulated significantly in patients with diabetes.If I asked you to pick the \"top three\" genes other than the ACE polymorphisms, which three would you choose and why?DR.ADLER: Well, actually I didn't see all of their results nor did they report all 182.But I guess my favorite ones would be some that relate to the ROS pathway because this is an all-purpose pathway of cell injury fueled by a hyperglycemic environment; some that relate to podocyte structure to explain the development of proteinuria; and TGF-b, which is a master regulator of sclerosis and fibrosis."
                }
            ],
            "ec62a4d9-2fe2-49b0-84d8-13b1597e2067": [
                {
                    "document_id": "ec62a4d9-2fe2-49b0-84d8-13b1597e2067",
                    "text": "IncRNAs and microRNAs\n\nFigure 1 | Emerging molecular mechanisms of diabetic nephropathy.Diabetic conditions induce the expression of growth factors such as transforming growth factor β1 and angiotensin II, cytokines and AGEs to promote inflammation, fibrosis and hypertrophy, which contribute to the progression of diabetic nephropathy.These factors stimulate various signal transduction mechanisms that activate downstream transcription factors.They can also affect DNA methylation and histone modifications, which result in increased chromatin accessibility to transcription factors near pathological genes in renal cells.Coordinated interactions between transcription factors and epigenetic mechanisms can increase the expression of not only coding RNAs, but also noncoding RNAs such as microRNAs and lncRNAs.Furthermore, microRNAs and lncRNAs can also increase the expression of pathological genes via post-transcriptional mechanisms.Notably, the induction of key coding genes and proteins, lncRNAs and microRNAs can also 'lock' open chromatin states to create persistent expression of genes, which could be one mechanism of metabolic memory.Abbreviations: AGE, advanced glycation end-product; lncRNA, long noncoding RNA."
                },
                {
                    "document_id": "ec62a4d9-2fe2-49b0-84d8-13b1597e2067",
                    "text": "Key points\n\n■ Diabetic conditions induce inflammation, fibrosis and hypertrophy in renal cells through various cytokines and growth factors such as transforming growth factor β1, angiotensin II and platelet-derived growth factor ■ The engagement of cytokines and growth factors with their receptors triggers signal transduction cascades that result in the activation of transcription factors to increase expression of inflammatory and fibrotic genes ■ These signalling mechanisms affect epigenetic states-such as DNA methylation and chromatin histone modifications-to augment the expression of profibrotic and inflammatory genes, as well as noncoding RNAs ■ Noncoding RNAs that are induced by diabetic conditions can also promote the expression of pathological genes via various post-transcriptional and post-translational mechanisms ■ These epigenetic mechanisms and noncoding RNAs can lead to persistently open chromatin structures at pathological genes and sustained gene expression, which can also be a mechanism for 'metabolic memory' ■ Key epigenetic regulators, microRNAs and long noncoding RNAs could serve as new therapeutic targets for diabetic nephropathy"
                },
                {
                    "document_id": "ec62a4d9-2fe2-49b0-84d8-13b1597e2067",
                    "text": "\n| Diabetic nephropathy (DN), a severe microvascular complication frequently associated with both type 1 and type 2 diabetes mellitus, is a leading cause of renal failure.The condition can also lead to accelerated cardiovascular disease and macrovascular complications.Currently available therapies have not been fully efficacious in the treatment of DN, suggesting that further understanding of the molecular mechanisms underlying the pathogenesis of DN is necessary for the improved management of this disease.Although key signal transduction and gene regulation mechanisms have been identified, especially those related to the effects of hyperglycaemia, transforming growth factor β1 and angiotensin II, progress in functional genomics, high-throughput sequencing technology, epigenetics and systems biology approaches have greatly expanded our knowledge and uncovered new molecular mechanisms and factors involved in DN.These mechanisms include DNA methylation, chromatin histone modifications, novel transcripts and functional noncoding RNAs, such as microRNAs and long noncoding RNAs.In this Review, we discuss the significance of these emerging mechanisms, how they mediate the actions of growth factors to augment the expression of extracellular matrix and inflammatory genes associated with DN and their potential usefulness as diagnostic biomarkers or novel therapeutic targets for DN."
                },
                {
                    "document_id": "ec62a4d9-2fe2-49b0-84d8-13b1597e2067",
                    "text": "\n\n| microRNAs relevant to the pathogenesis of diabetic nephropathy"
                },
                {
                    "document_id": "ec62a4d9-2fe2-49b0-84d8-13b1597e2067",
                    "text": "Review criteria\n\nA search for original published articles focusing on \"diabetic nephropathy\", \"signal transduction\", \"noncoding RNAs\", \"microRNAs\", \"long noncoding RNAs\", \"genetics\" and \"epigenetics\" was performed in MEDLINE and PubMed.All articles identified were English-language, full-text papers.We also searched the reference lists of identified articles for further relevant papers."
                }
            ]
        },
        "data_source": [
            {
                "document_id": "7ebf3dcf-0e9a-44d7-bd1c-1c49004d0753",
                "section_type": "main",
                "text": "\n\nAll these suggest towards important roles of various lncRNAs in complications associated with diabetes and, therefore, assume importance to be studied in detail."
            },
            {
                "document_id": "ec62a4d9-2fe2-49b0-84d8-13b1597e2067",
                "section_type": "main",
                "text": "IncRNAs and microRNAs\n\nFigure 1 | Emerging molecular mechanisms of diabetic nephropathy.Diabetic conditions induce the expression of growth factors such as transforming growth factor β1 and angiotensin II, cytokines and AGEs to promote inflammation, fibrosis and hypertrophy, which contribute to the progression of diabetic nephropathy.These factors stimulate various signal transduction mechanisms that activate downstream transcription factors.They can also affect DNA methylation and histone modifications, which result in increased chromatin accessibility to transcription factors near pathological genes in renal cells.Coordinated interactions between transcription factors and epigenetic mechanisms can increase the expression of not only coding RNAs, but also noncoding RNAs such as microRNAs and lncRNAs.Furthermore, microRNAs and lncRNAs can also increase the expression of pathological genes via post-transcriptional mechanisms.Notably, the induction of key coding genes and proteins, lncRNAs and microRNAs can also 'lock' open chromatin states to create persistent expression of genes, which could be one mechanism of metabolic memory.Abbreviations: AGE, advanced glycation end-product; lncRNA, long noncoding RNA."
            },
            {
                "document_id": "7e809821-000d-4fff-971d-264650e3612b",
                "section_type": "main",
                "text": "M A N U S C R I P T A C C E P T E D\n\nIn relation to the regulation of gene expression, the role of microRNAs (miRNAs) in diabetic retinopathy has been gaining more emphasis.miRNAs are non-coding small RNAs which modulate post-transcriptional control of gene expression through degradation or translational repression of key messenger RNAs.miRNAs can be detected in serum (free, associated with proteins or within membrane-bound particles) (Weiland et al., 2012), vitreous (Ragusa et al., 2013) and aqueous (Dunmire et al., 2013).As reviewed by Mastropasqua et al., miRNAs hold considerable interest for diabetic retinopathy since they can regulate important pathogenic responses such as angiogenesis, blood flow, neural cell dysfunction, tissue-specific inflammation and glucose metabolism (Mastropasqua et al., 2014).Although based on a small patient sample, it has been reported that three separate miRNAs (miR-21, miR-181c, and miR-1179) in serum of patients with diabetic retinopathy have potential to be used as biomarkers for early detection of disease (Li et al., 2014;Qing et al., 2014).While this is still a growing research area, miRNAs hold considerable clinical potential in the diabetic retinopathy field, both as possible drug-targets for regulation of dysfunctional cell responses and as diagnostic biomarkers."
            },
            {
                "document_id": "7ebf3dcf-0e9a-44d7-bd1c-1c49004d0753",
                "section_type": "main",
                "text": "Roles of lncRNAs in diabetic complications\n\nApart from being involved in major metabolic tissues during diabetes as discussed above, lncRNAs are implicated in complications associated with diabetes.Diabetic retinopathy is one of the common complications in diabetic patients, which leads to impaired or loss of vision.Altered expression of lncRNAs, namely MALAT1 [82,83] and MEG3 [84], are reported to be associated with diabetic retinopathy.In STZ-induced diabetic rats, the expression of MALAT1 is elevated in the endothelial cells of the retina and knockdown of MALAT1 ameliorates retinopathy in STZ-induced rats [82].The lncRNA, MEG3, was also found to be downregulated in the retina of STZ-induced diabetic mice and its in vitro knockdown in retinal endothelial cells was found to regulate cell proliferation, viability, and migration [84].Hyperglycemia as in diabetes causes upregulation of ANRIL levels in endothelial cells [85,86], and this elevates the levels of the PRC2 subunit, EZH2 that consequently promotes the expression of VEGF, a key promoter of angiogenesis [85].Another major complication associated with diabetes is diabetic nephropathy, and this is considered a major cause of end-stage renal disease and disability in diabetic patients [87].Recent studies show that lncRNAs play important roles in the development of diabetic nephropathy and accumulation of extracellular matrix (ECM) proteins.There is higher expression of the lncRNA, PVT1, during diabetic nephropathy, and this increase leads to increased fibrosis due to accumulation of ECM proteins in renal cells [88]; downregulation of PVT1 reduces ECM accumulation [88].LncRNA PVT1 is also a host to miR-1207-5p and this miRNA is shown to regulate the expression of fibronectin1 (FN1), plasminogen activator inhibitor-1 (PAI1), and transforming growth factor beta 1 (TGFβ1) [89].In renal tube injury during diabetes, the lncRNA, MIAT, is under-expressed, and this negatively correlates with creatinine and BUN levels in the serum of these subjects.It has been shown to regulate cell viability of proximal convoluted renal tubules [90].In diabetic nephropathic mice, the lncRNA, MGC, is increased in renal mesangial cells.Interestingly, this lncRNA harbours a cluster of approximately 40 miRNAs, and is regulated by the ER stress marker C/EBP homologous protein (CHOP) [91].In CHOP -deficient mice, there is decreased expression of the lncRNA, MGC, and the clustered miRNAs, and these mice have shown an improvement in diabetic nephropathy [91].Diabetic nephropathy is also associated with increased levels of lincRNA, Gm4419, and this exerts its action by interacting with NF-κβ.Knockdown of this lincRNA in renal mesangial cells lowers cellular proliferation and inhibits expression of NF-κβ in hyperglycemic states [92].The lncRNA, TUG1, that is upregulated in diabetic nephropathy acts as sponge for miR-377 and regulates PPAR-γ expression which further modulates the expression of FN1, collagen type IV alpha 1 chain (COL4A1), PAI1, and TGFβ1 in renal mesangial cells [93].Diabetic cardiomyopathy is a critical end-stage complication associated with diabetes.Several such cardiovascular complications and myocardial dysfunction in diabetic patients lead to heart failure [94].Differential expression analysis in cardiac tissue from normal and diabetic rats shows that the lncRNA, MALAT1, is upregulated during cardiomyopathy and knockdown of this lncRNA improves left ventricular systolic function by reducing myocardial inflammation in diabetic rats [95,96].Decreased expression of the lncRNA, H19, is also reported during diabetes [68,70], and this often results in decreased expression of the exonic miRNA, miR-675 [97,98].mir-675 directly targets the voltage-dependent anion channel 1 (VDAC1) which is involved in mitochondria-mediated apoptosis in the cardiac tissue during diabetes.H19 overexpression in diabetic rats reduces oxidative stress, apoptosis, and inflammation, and improves ventricle function [98].LncRNAs NONRATT021972 and uc.48+ are reported to be associated with diabetic neuropathic pain [99,100], and inhibition of both have been shown to alleviate such neuropathic pain by activating the P2X3 receptor.Impaired wound closure is a notable complication associated with diabetes and a recent report shows decreased levels of the lncRNA, Lethe in such impaired dorsal wounds of diabetic mice.This was demonstrated to be associated with increased ROS production, possibly through regulation of NOX2 expression [101]."
            },
            {
                "document_id": "ec62a4d9-2fe2-49b0-84d8-13b1597e2067",
                "section_type": "main",
                "text": "\n\n| microRNAs relevant to the pathogenesis of diabetic nephropathy"
            },
            {
                "document_id": "ec62a4d9-2fe2-49b0-84d8-13b1597e2067",
                "section_type": "main",
                "text": "Review criteria\n\nA search for original published articles focusing on \"diabetic nephropathy\", \"signal transduction\", \"noncoding RNAs\", \"microRNAs\", \"long noncoding RNAs\", \"genetics\" and \"epigenetics\" was performed in MEDLINE and PubMed.All articles identified were English-language, full-text papers.We also searched the reference lists of identified articles for further relevant papers."
            },
            {
                "document_id": "34184c8d-b167-4ae8-bfce-01e18d78fe41",
                "section_type": "main",
                "text": "Introduction\n\nDiabetes-related complications represent one of the most important health problems worldwide with dire social and economic projections (Cooper, 2012).One of the most important medical concerns of the diabetes epidemic is diabetic nephropathy (DN).Diabetic nephropathy is regarded as a prototypical disease of gene and environmental interactions because not all diabetic subjects with traditional risk factors develop clinically evident nephropathy, indicating a role for individual susceptibility.The majority (>85%) of GWAS-identified single nucleotide polymorphisms (SNPs) are located in the non-coding regions of the genome and thus their functional implication lies in identifying the target genes, cell types, and the mode of dysregulation caused by these non-coding SNPs (Maurano et al., 2012).Recent studies indicate that complex trait-causing variants localize to cell-type-specific, functionally important gene regulatory regions where they can disrupt or create transcription factor binding sites to alter transcript levels only in disease-target cell types (Ko and Susztak, 2013;Susztak, 2014).Several elements of the immune system including cytokines and resident chemokines, macrophage recruitment, T lymphocytes, and immune complex deposition have recently been associated with DN (Navarro-González and Mora-Fernández, 2008;Gaballa and Farag, 2013).Since renal cells are also capable of synthesizing pro-inflammatory cytokines such as tumor necrotic factor-alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), therefore, these cytokines acting in a paracrine or autocrine manner may induce significant effects leading to the development and progression of several renal disorders (Matoba et al., 2010;Pruijm et al., 2012;Shankar et al., 2011).The rationale of this study involved a concerted effort of genotyping, correlation and gene expression techniques involving three pro-inflammatory cytokine genes  in the development and progression of DN as well as identification of high risk patients involving susceptibility or poor clinical outcome."
            },
            {
                "document_id": "2dc80127-89ba-47be-9e94-d90c2105be8d",
                "section_type": "main",
                "text": "\n\nNumerous recent reports have demonstrated abnormal expression of various miRNAs in renal, vascular and retinal cells under diabetic conditions, and in vivo models of related diabetic complications [8,[87][88][89][90][91]. Notably, the functional relevance of these miRNAs has been highlighted by the fact they target key genes associated with the progression of, or protection against, these complications.In particular, the role of miRNAs in diabetic nephropathy has been extensively studied, including in the actions of TGF-β related to fibrosis and other key renal outcomes in vitro and in vivo [8,[87][88][89][90].In diabetic retinopathy, several miRNAs have been reported to modulate the disease by targeting factors associated with angiogenesis, inflammation, and oxidant stress in RECs and in diabetic retinas [88,89].Reports have also implicated various miRNAs in the aberrant expression of genes associated with diabetic cardiomyopathy [88,91].In addition, effective in vivo targeting of miRNAs has now been demonstrated thanks to advances in nucleotide chemistry and the design of nuclease-resistant anti-miRNAs, which suggest future translational potential of miRNA-based therapies for human diabetic complications [8].Importantly, since miRNAs are stable in biological fluids such as urine and serum [8], they are being assessed in samples from various clinical cohorts as valuable biomarkers for the early detection of diabetic complications, for which there is a major unmet clinical need.It is clear that research in the field of miRNAs and diabetic complications will continue at a rapid pace."
            },
            {
                "document_id": "ec62a4d9-2fe2-49b0-84d8-13b1597e2067",
                "section_type": "main",
                "text": "Key points\n\n■ Diabetic conditions induce inflammation, fibrosis and hypertrophy in renal cells through various cytokines and growth factors such as transforming growth factor β1, angiotensin II and platelet-derived growth factor ■ The engagement of cytokines and growth factors with their receptors triggers signal transduction cascades that result in the activation of transcription factors to increase expression of inflammatory and fibrotic genes ■ These signalling mechanisms affect epigenetic states-such as DNA methylation and chromatin histone modifications-to augment the expression of profibrotic and inflammatory genes, as well as noncoding RNAs ■ Noncoding RNAs that are induced by diabetic conditions can also promote the expression of pathological genes via various post-transcriptional and post-translational mechanisms ■ These epigenetic mechanisms and noncoding RNAs can lead to persistently open chromatin structures at pathological genes and sustained gene expression, which can also be a mechanism for 'metabolic memory' ■ Key epigenetic regulators, microRNAs and long noncoding RNAs could serve as new therapeutic targets for diabetic nephropathy"
            },
            {
                "document_id": "d23e9456-8ee8-46e0-9870-18ff69965c28",
                "section_type": "main",
                "text": "miRNAs in Kidney Disease and Diabetic Nephropathy\n\nDiabetic nephropathy is a progressive kidney disease and a major debilitating complication of both type 1 and type 2  diabetes that can lead to end-stage renal disease (ESRD) and related cardiovascular disorders.Absence or lower levels of particular miRNAs in the kidney compared with other organs may permit renal specific expression of target proteins that are important for kidney functions [45].Figure 4 depicts the connection between the role of miRNAs and kidney fibrosis.Altered expression of miRNAs causes renal fibrosis by inducing EMT, EndMT, and other fibrogenic stimuli.The accumulative effects of hyperglycaemia, inflammatory cytokines, proteinuria, ageing, high blood pressure, and hypoxia result into alteration of miRNAs expression profiles.The altered miRNAs level causes the initiation of such transition program in normal kidney, finally fibrosis.Some of the miRNAs that are more abundant in the kidney compared with other organs include miR-192, miR-194, miR-204, miR-215, and miR-216.A critical role of miRNA regulation in the progression of glomerular and tubular damage and the development of proteinuria been suggested by studies in mice with podocytespecific deletion of Dicer [46].There was a rapid progression of renal disease with initial development of albuminuria followed by pathological features of glomerulosclerosis and tubulointerstitial fibrosis.It is likely that these phenotypes are due to the global loss of miRNAs because of Dicer deletion, but, given multiple miRNAs and their myriad targets, the precise pathways responsible require identification.These investigators also identified specific miRNA changes, for example, the downregulation of the miR-30 family when Dicer was deleted.Of relevance, the miR-30 family was found to target connective tissue growth factor, a profibrotic molecule that is also downstream of transforming growth factor (TGF)- [47].Thus, the targets of these miRNAs may regulate critical glomerular and podocyte functions.These findings have also been complemented by an elegant study revealing a developmental role for the miR-30 family during pronephric kidney development in Xenopus [48].Sun et al. [49] identified five miRNAs (-192, -194, -204, -215, and -216) that were highly expressed in human and mouse kidney using miRNA microarray.A recent report using new proteomic approaches to profile and identify miRNA targets demonstrated that miR-NAs repress their targets at both the mRNA and translational levels and that the effects are mostly relatively mild [50].The role of miR-192 remains controversial and highlights the complex nature of miRNA research.Kato et al. [51] observed increased renal expression of miR-192 in streptozotocin-(STZ-) induced diabetes and in the db/db mouse and demonstrated that transforming growth factor (TGF-1) upregulated miR-192 in mesangial cells (MCs).miR-192 repressed the translation of Zeb2, a transcriptional repressor that binds to the E-box in the collagen 12 (col12) gene.They proposed that miR-192 repressed Zeb2 and resulted in increased col12 expression in vitro and contributed to increased collagen deposition in vivo.These data suggest a role for miR-192 in the development of the matrix accumulation observed in DN.It is interesting that the expression of miR-192 was increased by TGF- in mouse MCs (mesangial cells), whereas, conversely, the expression of its target, Zeb2, was decreased [51].This also paralleled the increased Col1 2 and TGF- expression [51].These results suggested that the increase in TGF- in vivo in diabetic glomeruli and in vitro in MCs can induce miR-192 expression, which can target and downregulate Zeb2 thereby to increase Col1 2.This is supported by the report showing that miR-192 is upregulated in human MCs treated with high glucose [51].TGF- induced downregulation of Zeb2 (via miR-192) and Zeb1 (via potentially another miRNA) can cooperate to enhance Col1 2 expression via de-repression at E-box elements [51].In contrast to the above, other reports suggest the relationship between miR-192 and renal fibrosis may be more complicated.Krupa et al. [52] identified two miRNAs in human renal biopsies, the expression of which differed by more than twofold between progressors and nonprogressors with respect to DN, the greatest change occurring in miR-192 which was significantly lower in patients with advanced DN, correlating with tubulointerstitial fibrosis and low glomerular filtration rate.They also reported, in contrast to the Kato et al. [51] study in MCs, that TGF-1 decreased expression of miR-192 in cultured proximal tubular cells (PTCs).These investigators concluded that a decrease in miR-192 is associated with increased renal fibrosis in vivo.Interestingly, connective tissue growth factor (CTGF) treatment also resulted in fibrogenesis but caused the induction of miR-192/215 and, consequently, decreased Zeb2 and increased E-cadherin.The contrasting findings above highlight the complex nature of miRNA research.Some of the differences may relate to models and/or experimental conditions; however, one often overlooked explanation is that some effects of miRNAs and inhibitors are likely to be indirect in nature.A recent report also showed that BMP6-induced miR-192 decreases the expression of Zeb1 in breast cancer cells [53].Thus, TGF- induced increase in the expression of key miRNAs (miR-192 and miR-200 family members) might coordinately downregulate E-box repressors Zeb1 and Zeb2 to increase Col12 expression in MCs related to the pathogenesis of DN.The proximal promoter of the Col1a2 gene responds to TGF- via smads and SP1.Conversely, the downregulation of Zeb1 and Zeb2 by TGF- via miR-200 family and miR-192 can affect upstream E-box regions.Because E-boxes are present in the upstream genomic regions of the miR-200 family, miR-200 family members may themselves be regulated by Zeb1 and Zeb2 [54].It is possible that the miR-200 family upregulated by TGF- or in diabetic glomeruli under early stages of the disease can also regulate collagen expression related to diabetic kidney disease by targeting and downregulating E-box repressors.miR-192 might initiate signaling from TGF- to upregulate miR-200 family members, which subsequently could amplify the signaling by further regulating themselves through down regulation of Ebox repressors.Such events could lead to progressive renal dysfunction under pathologic conditions such as diabetes, in which TGF- levels are enhanced.Conversely, there are several reports that miR-200 family members and miR-192 can be suppressed by TGF-, and this promotes epithelial-tomesenchymal transition (EMT) in cancer and other kidneyderived epithelial cell lines via subsequent upregulation of targets Zeb1 and Zeb2 to repress E-cadherin [54,55]."
            },
            {
                "document_id": "18a35699-873a-4542-b35a-3a4a14edd628",
                "section_type": "main",
                "text": "\n\nPlatelets are key partaker in CVD and their involvement in the development of cardiovascular complications is strengthened in diabetes (148).Platelets play an important role in the pathophysiology of thrombosis and represent an important source of different RNA species, including pseudogenes, intronic transcripts, non-coding RNAs, and antisense transcripts (149,150).These molecules can be released by platelets through microvescicles, contributing to the horizontal transfer of molecular signals delivered through the bloodstream to specific sites of action (151).The downregulation of miR-223, miR-126, or 146a observed in diabetic and hyperglycemic patients (137,152) has been associated with increased platelet reactivity and aggregation (153,154).In line with these findings, silencing of miR-223 in mice caused a hyperreactive and hyperadhesive platelet phenotype, and was associated with calpain activation through the increased expression of beta1 integrin, kindlin-3, and factor XIII (153,155).Moreover, the modulation of the expression levels of platelet miRNAs can also be measured in plasma.In fact, plasma levels of miR-223 and miR-126 are decreased in diabetics (137,156).This leads to the upregulation of the P2Y12 receptor, as well as P-selectin, further contributing to platelet dysfunction (156).As a result of this interaction, activation level of platelets in type 2 DM is increased (149,156,157).Consistently with this, circulating miR-223 levels are independent predictors of high on-treatment platelet reactivity (158).Another interesting mechanism linking platelets and diabetes involves miR-103b, a platelet-derived biomarker proposed for the early diagnosis of type 2 DM, and the secreted frizzledrelated protein-4 (SFRP4), a potential biomarker of early β cell dysfunction and diabetes.In fact, platelet-derived miR-103b is able to downregulate SFRP4, whose expression levels are significantly increased in pancreatic islets and in the blood of patients with prediabetes or overt diabetes (159).These interesting results identify miR-103b as a novel potential marker of prediabetes and diabetes, and disclose a novel potential therapeutic target in type 2 DM."
            },
            {
                "document_id": "02a9d5a9-41a4-4d70-b828-c4bda13fa01c",
                "section_type": "main",
                "text": "\n\nIt is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication.Targeting early features of DN, including renal extracellular matrix accumulation (ECM) and glomerular hypertrophy, can prevent disease progression.Here we show that a megacluster of nearly 40 microRNAs and their host long non-coding RNA transcript (lnc-MGC) are coordinately increased in the glomeruli of mouse models of DN, and mesangial cells treated with transforming growth factor-b1 (TGF-b1) or high glucose.Lnc-MGC is regulated by an endoplasmic reticulum (ER) stress-related transcription factor, CHOP.Cluster microRNAs and lnc-MGC are decreased in diabetic Chop À / À mice that showed protection from DN. Target genes of megacluster microRNAs have functions related to protein synthesis and ER stress.A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice.Relevance to human DN is also demonstrated.These results demonstrate the translational implications of targeting lnc-MGC for controlling DN progression."
            },
            {
                "document_id": "02a9d5a9-41a4-4d70-b828-c4bda13fa01c",
                "section_type": "abstract",
                "text": "\nIt is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication.Targeting early features of DN, including renal extracellular matrix accumulation (ECM) and glomerular hypertrophy, can prevent disease progression.Here we show that a megacluster of nearly 40 microRNAs and their host long non-coding RNA transcript (lnc-MGC) are coordinately increased in the glomeruli of mouse models of DN, and mesangial cells treated with transforming growth factor-b1 (TGF-b1) or high glucose.Lnc-MGC is regulated by an endoplasmic reticulum (ER) stress-related transcription factor, CHOP.Cluster microRNAs and lnc-MGC are decreased in diabetic Chop À / À mice that showed protection from DN. Target genes of megacluster microRNAs have functions related to protein synthesis and ER stress.A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice.Relevance to human DN is also demonstrated.These results demonstrate the translational implications of targeting lnc-MGC for controlling DN progression."
            },
            {
                "document_id": "80e1b2af-be79-4d9b-852f-46bf3e23c963",
                "section_type": "main",
                "text": "\n\nAn overall important consideration in study design is that similar to RNA, noncoding RNAs are tissue and cell specific [24,[77][78][79][80][81][82].Given that it is still unknown if pathogenic changes in AMD are localized to specific ocular tissues or systemic, one must take into consideration that potential biomarkers identified in the peripheral blood as \"disease associated\" may not reflect the disease mechanism occurring in the neural retina and/or RPE."
            },
            {
                "document_id": "e66846a6-1546-481b-baae-a55fc524c8af",
                "section_type": "main",
                "text": "\n\nDR. HARRINGTON: You mentioned Liu's data from China [abstract; Liu Z-H et al J Am Soc Nephrol 14:400A, 2003], which overwhelmed me.Apparently there are 182 genes whose expression is up-or down-regulated significantly in patients with diabetes.If I asked you to pick the \"top three\" genes other than the ACE polymorphisms, which three would you choose and why?DR.ADLER: Well, actually I didn't see all of their results nor did they report all 182.But I guess my favorite ones would be some that relate to the ROS pathway because this is an all-purpose pathway of cell injury fueled by a hyperglycemic environment; some that relate to podocyte structure to explain the development of proteinuria; and TGF-b, which is a master regulator of sclerosis and fibrosis."
            },
            {
                "document_id": "5d2fa6b9-8412-43cb-bc86-e9bcda73a4ef",
                "section_type": "main",
                "text": "They also identified enrichment in coagulation and\ncomplement pathways, signaling pathways, tissue remodeling, and antigen presentation, including PI3K-Akt, Rap1,\nToll-like, and NOD-like.  Sun et al.  [25] studied diabetic retinopathy and identified four stress-inducible genes Rmb3,\nCirbp, Mt1, and Mt2 which commonly exist in most retinal\ncell types.  Diabetes increases the inflammatory factor gene\nexpressions in retinal microglia and stimulates the immediate early gene expressions (IEGs) in retinal astrocytes.\n Van Zyl et al.  [30] studied glaucoma cases and identified\nthe cell types that represent gene expressions implicated in\nglaucoma."
            },
            {
                "document_id": "6011e960-6a6e-47fe-94f2-2c21c224fd25",
                "section_type": "main",
                "text": "\n\nOne of the major problems facing clinical nephrology currently throughout the world is an exponential increase in patients with end-stage renal disease (ESRD), which is largely related to a high incidence of diabetic nephropathy.The latter is characterized by a multitude of metabolic and signaling events following excessive channeling of glucose, which leads to an increased synthesis of extracellular matrix (ECM) glycoproteins resulting in glomerulosclerosis, interstitial fibrosis and ultimately ESRD.With the incidence of nephropathy at pandemic levels and a high rate of ESRD, physicians around the world must treat a disproportionately large number of diabetic patients with upto-date innovative measures.In this regard, identification of genes that are crucially involved in the progression of diabetic nephropathy would enhance the discovery of new biomarkers and could also promote the development of novel therapeutic strategies.Over the last decade, we focused on the recent methodologies of high-throughput and genome-wide screening for identification of relevant genes in various animal models, which included the following: (1) single nucleotide polymorphism-based genome-wide screening; (2) the transcriptome approach, such as differential display reverse transcription polymerase chain reaction (DDRT-PCR), representational difference analysis of cDNA (cDNA-RDA)/suppressive subtractive hybridization, SAGE (serial analysis of gene expression) and DNA Microarray; and (3) the proteomic approach and 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) coupled with mass spectroscopic analysis.Several genes, such as Tim44 (translocase of inner mito-chondrial membrane-44), RSOR/MIOX (renal specific oxidoreductase/myo-inositol oxygenase), UbA52, Rap1b (Ras-related GTPase), gremlin, osteopontin, hydroxysteroid dehydrogenase-3β isotype 4 and those of the Wnt signaling pathway, were identified as differentially expressed genes in kidneys of diabetic rodents.Functional analysis of these genes and the subsequent translational research in the clinical settings would be very valuable in the prevention and treatment of diabetic nephropathy.Future trends for identification of the biomarkers and therapeutic target genes should also include genome scale DNA/histonemethylation profiling, metabolomic approaches (e.g.metabolic phenotyping by 1H spectroscopy) and lectin microarray for glycan profiling along with the development of robust data-mining strategies."
            },
            {
                "document_id": "88dde947-5255-40e1-92d5-afde089b517b",
                "section_type": "main",
                "text": "\n\nSkol et al. developed methods to study genomics and transcriptomics together to help discover genes that cause diabetic retinopathy.Genes involved in how cells respond to high blood sugar were first identified using cells grown in the lab.By comparing the activity of these genes in people with and without retinopathy the study identified genes associated with an increased risk of retinopathy in diabetes.In people with retinopathy, the activity of the folliculin gene (FLCN) increased more in response to high blood sugar.This was further verified with independent groups of people and using computer models to estimate the effect of different versions of the folliculin gene."
            },
            {
                "document_id": "6011e960-6a6e-47fe-94f2-2c21c224fd25",
                "section_type": "abstract",
                "text": "\nOne of the major problems facing clinical nephrology currently throughout the world is an exponential increase in patients with end-stage renal disease (ESRD), which is largely related to a high incidence of diabetic nephropathy.The latter is characterized by a multitude of metabolic and signaling events following excessive channeling of glucose, which leads to an increased synthesis of extracellular matrix (ECM) glycoproteins resulting in glomerulosclerosis, interstitial fibrosis and ultimately ESRD.With the incidence of nephropathy at pandemic levels and a high rate of ESRD, physicians around the world must treat a disproportionately large number of diabetic patients with upto-date innovative measures.In this regard, identification of genes that are crucially involved in the progression of diabetic nephropathy would enhance the discovery of new biomarkers and could also promote the development of novel therapeutic strategies.Over the last decade, we focused on the recent methodologies of high-throughput and genome-wide screening for identification of relevant genes in various animal models, which included the following: (1) single nucleotide polymorphism-based genome-wide screening; (2) the transcriptome approach, such as differential display reverse transcription polymerase chain reaction (DDRT-PCR), representational difference analysis of cDNA (cDNA-RDA)/suppressive subtractive hybridization, SAGE (serial analysis of gene expression) and DNA Microarray; and (3) the proteomic approach and 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) coupled with mass spectroscopic analysis.Several genes, such as Tim44 (translocase of inner mito-chondrial membrane-44), RSOR/MIOX (renal specific oxidoreductase/myo-inositol oxygenase), UbA52, Rap1b (Ras-related GTPase), gremlin, osteopontin, hydroxysteroid dehydrogenase-3β isotype 4 and those of the Wnt signaling pathway, were identified as differentially expressed genes in kidneys of diabetic rodents.Functional analysis of these genes and the subsequent translational research in the clinical settings would be very valuable in the prevention and treatment of diabetic nephropathy.Future trends for identification of the biomarkers and therapeutic target genes should also include genome scale DNA/histonemethylation profiling, metabolomic approaches (e.g.metabolic phenotyping by 1H spectroscopy) and lectin microarray for glycan profiling along with the development of robust data-mining strategies."
            },
            {
                "document_id": "961f88ba-2090-4904-942c-f0e014bbe53f",
                "section_type": "main",
                "text": "\n\nDescription of some problems associated with diabetes and possible nanomedicine solutions."
            },
            {
                "document_id": "6011e960-6a6e-47fe-94f2-2c21c224fd25",
                "section_type": "main",
                "text": "Newly Identified Genes Relevant in the Progression of Diabetic Nephropathy\n\nThe cellular events such as increased flux of polyols and hexosamines; generation of AGEs; increased activity of PKC, transforming growth factor-β-Smad-MAPK (mitogen-activated protein kinase) pathway and GTP-binding proteins; G1 cell cycle arrest associated with altered expression of cyclin kinases and their inhibitors; and generation of ROS are responsible for a final outcome of increased synthesis and deposition of ECM.The ROS, whether mitochondrial or cell membrane-derived, are also responsible for the activation of the renin-angiotensin system that eventually contributes to glomerular hyperfiltration and subsequent renal fibrosis (fig. 1) [71].In addition to these macromolecules, newly identified genes, such as RSOR/MIOX, Tim44 and Rap1b, may also be an integral part of the hyperglycemia-induced cytosolic and mitochondrial processes that culminate in the development of diabetic nephropathy [48][49][50][51][52][53][54][55]."
            },
            {
                "document_id": "18a35699-873a-4542-b35a-3a4a14edd628",
                "section_type": "main",
                "text": "\n\nIn vitro and in vivo studies concerning the mechanisms that are responsible for the endothelial dysfunction in diabetes demonstrated that, in the presence of high glucose concentrations, upregulation of miR-185 reduced the expression of the glutathione peroxidase-1 (GPx-1) gene, which encodes an enzyme that is important in the prevention of oxidative stress (129); instead upregulation of miR-34a and miR-204 contributed to endothelial cell senescence by impairing SIRT-1 expression and function (130,131).In the endothelium, miR-126 exerts proangiogenic, and anti-inflammatory activities.At a functional level, it enhances VEGF and fibroblast growth factor activities, contributing to vascular integrity and angiogenesis (132,133), recruits progenitor cells through the chemokine CXCL12 (134), while it suppresses inflammation by inhibiting TNF-α, ROS, and NADPH oxidase via HMGB1 (135).Consistently, miR-126 levels are down-regulated in both myocardial tissue and plasma from type 2 diabetic patients without any known anamnestic data for CVD (136,137), and in patients with CAD (138), suggesting that it could represent a new diagnostic marker for diabetes and CVD.Other studies in endothelial colony-forming cells, as well as in progenitor endothelial cells (EPCs) exposed to high glucose, demonstrated that miR-134 and miR-130a affected cell motility and apoptosis, respectively (139,140)."
            },
            {
                "document_id": "42e06cda-627e-46f2-a289-c4c1fb6af8f2",
                "section_type": "main",
                "text": "Discussion\n\nAs is known, several mechanisms, mainly related to the dysfunction of the endothelium and smooth muscles, have been proposed in the aetiology of T2DMED.In this study, the four differentially expressed miRNAs may also be involved in the regulation of the endothelium and smooth muscle function based on a literature review.Numerous studies have reported their function in pathophysiological processes, such as cellular development, differentiation, and apoptosis, which are all essential mechanisms of T2DMED (Beaumont et al. 2014;Girard et al. 2008;Komatsu et al. 2014;Lee et al. 2012;Liu et al. 2008;Shan et al. 2010;Sweetman et al. 2006).Importantly, miR-206 may be involved in diabetes-associated complications by contributing to high glucose-mediated apoptosis (Shan et al. 2010), and miR-133a has anti-apoptosis effects (Xu et al. 2007).In addition, miR-133a and miR-206 are muscle-specific miRNAs (Chen et al. 2012;Liu et al. 2008) and thus could regulate muscular cell functions, such as the augmentation of smooth muscle contraction by miR-133a (Chiba et al. 2009).Additionally, miR-18a could also increase vascular smooth muscle cell differentiation (Kee et al. 2014)."
            },
            {
                "document_id": "230022b2-931e-42ab-b100-5e9776483d1a",
                "section_type": "main",
                "text": "| DISCUSSION\n\nThis study examined retinas from WT and diabetic SD male rats to investigate the changes in a variety of retinal transcripts as a result of diabetes using RNA-seq.We identified a total of 118 DEGs, of which 72 were up-regulated and 46 were down-regulated.We also found 66 GO terms and 41 KEGG pathways which were significantly enriched by GO and KEGG analysis.Top 10 most down-regulated and up-regulated genes are listed in Tables 3 and 4, and were confirmed by qRT-PCR showed in Figure 4. Asb15 gene is the most up-regulated one we identified and confirmed.Asb15 is a member of Asb gene family; the family has been reported to be involved in cell proliferation and differentiation (Hancock et al., 1991;Kohroki et al., 2001;Liu et al., 2003).The presence of both Ankyrin repeat and suppressors of cytokine signaling (SOCS) box motifs are characters of members of Asb gene family (McDaneld, Hancock, & Moody, 2004).Member of SOCS family plays important roles in the negative regulation of signaling pathways (Kile & Alexander, 2001;Zhang et al., 2001).SOCS3 acts as a regulator of inflammation through inhibiting JAK/STAT pathway (Tamiya, Kashiwagi, & Takahashi, 2011).Down-regulating SOCS3-STAT3 can alleviate DR (Chen, Lv, & Gan, 2017;Jiang, Thaksan, & Bheemreddy, 2014;Ye & Steinle, 2015).Ladinin-1(Lad1), a largely uncharacterized protein to date, was found to be related to the proliferation and migration of breast cancer cells (Roth, Srivastava, & Lindzen, 2018).Cell proliferation and migration are processes of neovascularization.Neovascularization is the sign of PDR, which can lead to serious vision loss of patients.Fibroblast growth factor 2 (Fgf2) is a member of fibroblast growth factors (FGFs) family.FGFs and their receptors have important roles in cell proliferation, migration, differentiation, and survival (Saichaemchan, Ariyawutyakorn, & Varella-Garcia, 2016).FGF2 was found overexpression in the early stage of DR, and it can destroy the blood-retinal barrier (Yang et al., 2018).Hemoglobin alpha adult chain 1 (Hba-a1) is one of the hemoglobin genes.Hemoglobin plays an important role in neuronal respiration, oxidative stress, and response to injury (He et al., 2010;Poh, Yeo, Stohler, & Ong, 2012;Richter, Meurers, Zhu, Medvedeva, & Chesselet, 2009).Neuronal respiration is an important life activity of neuronal cells.Neurological injury is one of the performances of DR.Inositol monophosphatase domain containing 1 (Impad1) encodes gPAPP, which is a Golgi-resident nucleotide phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the by-product of sulfotransferase reactions, to AMP.AMP-activated protein kinase (AMPK) signaling pathway plays vital roles in the diabetes-induced retinal inflammation (Kubota, Ozawa, & Kurihara, 2011).RT1-Bb, RT1-Ba, belongs to RT1 complex, which is the major histocompatibility complex (MHC) of rat (Eberhard & Lutz, 2001).It is believed that the MHC region is vital because it plays an important role in diseases, such as autoimmune and infectious diseases, vascular diseases like DR, hematological and neurological diseases (John, 2005).Collagen type III alpha 1 chain (Col3a1) is a kind of type III collagen, mainly existing in the extracellular matrix.Lacking of type III collagen can destroy the structure of connective tissues (Cortini et al., 2017).According to previous researches, it is associated with the aneurysm.Retinal microaneurysm is the early performance of DR.Col3a1 was also found significantly changed in RNA-seq of human PDR fibrovascular membranes (Lam et al., 2017).αA-crystallin (Cryga) and αF-crystallin (Crygf) are members of crystallins, which were involved in different functions in various tissues (Clayton, Jeanny, Bower, & Errington, 1986;Head, Peter, & Clayton, 1991;Smolich, Tarkington, Saha, & Grainger, 1994).Knockout of αA-crystallin can inhibit ocular neovascularization (Xu, Bai, & Huang, 2015).More and more evidence indicated that inflammation (Adamis, 2002;Gologorsky, Thanos, & Vavvas, 2012) and neovascularization (Gardner & Davila, 2017;Nguyen et al., 2018) are important in the pathogenesis of DR.The results of the KEGG pathway significant enrichment analysis revealed two most enrichment items-cell adhesion molecules (CAMs) and PI3K-Akt signaling pathway.CAMs are proteins located on cell surface; the binding of CAMs to their receptors is important in the mediation of inflammatory and immune reactions (Golias et al., 2007).Previous studies have suggested that CAMs are important in the development of DR (Khalfaoui et al., 2009;Ugurlu et al., 2013) of insulin and is associated with DR neovascularization (Qin, Zhang, & Xu, 2015;Sasore, Reynolds, & Kennedy, 2014)."
            },
            {
                "document_id": "ec62a4d9-2fe2-49b0-84d8-13b1597e2067",
                "section_type": "abstract",
                "text": "\n| Diabetic nephropathy (DN), a severe microvascular complication frequently associated with both type 1 and type 2 diabetes mellitus, is a leading cause of renal failure.The condition can also lead to accelerated cardiovascular disease and macrovascular complications.Currently available therapies have not been fully efficacious in the treatment of DN, suggesting that further understanding of the molecular mechanisms underlying the pathogenesis of DN is necessary for the improved management of this disease.Although key signal transduction and gene regulation mechanisms have been identified, especially those related to the effects of hyperglycaemia, transforming growth factor β1 and angiotensin II, progress in functional genomics, high-throughput sequencing technology, epigenetics and systems biology approaches have greatly expanded our knowledge and uncovered new molecular mechanisms and factors involved in DN.These mechanisms include DNA methylation, chromatin histone modifications, novel transcripts and functional noncoding RNAs, such as microRNAs and long noncoding RNAs.In this Review, we discuss the significance of these emerging mechanisms, how they mediate the actions of growth factors to augment the expression of extracellular matrix and inflammatory genes associated with DN and their potential usefulness as diagnostic biomarkers or novel therapeutic targets for DN."
            },
            {
                "document_id": "72aa5d47-336b-4e4f-8593-ee215b8891d2",
                "section_type": "main",
                "text": "\n\nThe current study takes an important first step towards this goal by identifying specific sets of genes whose expression accurately classifies patient samples with regard to diabetic neuropathy progression and by analysing their interactions within known cellular pathways.Identifying common elements in these complex networks will yield novel insights into disease pathogenesis, provide new therapeutic targets and identify potential diabetic neuropathy biomarkers.The genes identified in the current study confirm data gathered from experimental models of diabetes and provide a comprehensive picture of the expression of multiple targets in a single human tissue sample."
            },
            {
                "document_id": "a7bad429-5f6a-464f-a666-f9cb1be60338",
                "section_type": "main",
                "text": "\n\nFurthermore, the alpha kinase 1 gene (ALPK1) identified as a susceptibility gene for chronic kidney disease by GWAS [202] , was demonstrated in type 2 diabetes patients [203] .Three additional genes have been strongly correlated with this risk of diabetic retinopathy (DR) including the vascular endothelial growth receptor, aldose reductase and the receptor for advanced glycation products genes [204] where specific polymorphisms in these genes seem to increase the risk of DR development in diabetes patients [204] .A significant differential proteome (involving 56 out of 252 proteins) is evident that characterizes vitreous samples obtained from diabetes patients with the complication in comparison to diabetes patients without the complication and control individuals [205] .Interestingly, a large portion of these proteins (30 proteins) belong to the kallikrein-kinin, coagulation and complement systems including complement C3, complement factor 1, prothrombin, alpha-1antitrypsin and antithrombin III that are elevated in diabetic patients with retinopathy [205] .In addition, 2 single nucleotides polymorphisms in the human related B7-I gene seem to mediate podocyte injury in diabetic nephropathy [206] .Furthermore, increased concentration of the ligand of B7-1 correlates with the progression of end-stage renal disease (ESRD) in diabetes patients [206] .These results indicate that B7-I inhibition may serve as a potential target for diabetes nephropathy prevention and/or treatment.Recently, it was shown that direct correlation is evident between circulating levels of tumor necrosis factors 1 and 2 and increased risk of ESRD in American Indian patients [207] .The link between diabetes and proper bone development and health is evident.Studies using animal models with major significant reduction in insulin receptor (IR) in osteoprogenitor cells resulted in thin and rod-like weak bones with high risk of fractures [208] .Similar findings were observed in animal models with bone-specific IR knockdown animals which points to the central role of IR in the proper development of bones [208] .Type 2 diabetes is also associated with mitochondrial dysfunction in adipose tissues.Using knockout animal models of specific mitochondrial genes led to significant reduction in key electron transport complexes expression and eventually adipocytes death [209] .These animals exhibited Insulin resistance in addition to other complications that can potentially lead to cardiovascular disease [209] ."
            },
            {
                "document_id": "41fc22ce-f0dc-4d81-a2b5-14c563c7c767",
                "section_type": "main",
                "text": "Metabolism:\nA novel shared link between diabetes mellitus and Alzheimer’s disease.  J. Diabetes\nRes.  2020:4981814. doi: 10.1155/2020/4981814\n\nLiu, C., Hu, J., Zhao, N., Wang, J., Wang, N., Cirrito, J. R., et al.  (2017).\n Astrocytic LRP1 mediates brain abeta clearance and impacts amyloid deposition.\n J. Neurosci.  37, 4023–4031.  doi: 10.1523/JNEUROSCI.3442-16.2017\n\nWainberg, M., Sinnott-Armstrong, N., Mancuso, N., Barbeira, A., Knowles,\nD., Golan, D., et al.  (2019).  Opportunities and challenges for transcriptome-wide\nassociation studies.  Nat.  Genet.  51, 592–599.  doi: 10.1038/s41588-019-0385-z\n\nLiu, Q., Trotter, J., Zhang, J., Peters, M. M., Cheng, H., Bao, J., et al.  (2010)."
            },
            {
                "document_id": "e66846a6-1546-481b-baae-a55fc524c8af",
                "section_type": "main",
                "text": "\n\nI should underscore the fact that this discussion has been a simplified review of the relationships among glycemia, the RAS, histopathologic change, and the genetics of diabetic nephropathy, but its simplification allows us to underscore certain principles.In the redundant path of this biology, angiotensin II stimulates and interacts with a large number of other molecules.These are just a few of the major ones: glut-1, tumor necrosis factora (TNF-a), platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), advanced glycosylation end products (AGEs) (pentosidine), reactive oxygen species (ROS), oxidized low-density lipoprotein (LDL), vascular cell adhesion molecule (VCAM-1), osteopontin, NF-jB, RANTES (particularly in glomerular endothelial cells), and monocyte chemotactic protein (MCP).In closing, I'd like to leave you with the top 10 principles detailed by this discussion: (1) signaling systems, with their complexity and redundancy, are systems of great beauty, reflective of evolutionary order; (2) differentiated biologic tissues often use the same tools to achieve tissue-specific functions and express tissue-specific pathology; (3) diabetic nephropathy reflects cellular injury due to common biologic pathways manifested in different cell types/regions of the kidney; (4) the kidney's susceptibility to glomerulosclerosis and tubulointerstital fibrosis reflects the impact of the renal RAS and its interactions with other profibrotic molecular pathways; (5) defining these interactions and the downstream signaling mechanisms mediating them lays the foundation for discovering needed therapies beyond glycemic control and angiotensin II inhibition for the treatment of diabetic nephropathy; (6) signaling pathways downstream of angiotensin II represent prime targets for additional therapeutic interventions; (7) hypothesis-driven basic research on individual pathways has (and likely will continue to) shed light on the complexities of the pathologic interactions and the redundancies in the systems; (8) candidate gene studies are the genetic analogues of this type of hypothesis-driven basic research; (9) microarray and genomic scanning coupled with informatics technology offer the possibility of modeling these complex system interactions and hopefully will allow us to identify optimal targets for inhibition and/or up-regulation that can prevent progression and restore structure and function; and (10) given the redundancy and convergence of these pathways, the challenge will be in graded inhibition that will preserve salutary pathways, but inhibit deleterious ones."
            },
            {
                "document_id": "88dde947-5255-40e1-92d5-afde089b517b",
                "section_type": "main",
                "text": "\n\nIn this article, we identify genes whose expression responds differently to glucose in cells derived from T1D individuals with and without diabetic retinopathy.We show that one of these genes, folliculin (FLCN), is causally implicated in diabetic retinopathy based on results from genetic association testing and Mendelian randomization."
            },
            {
                "document_id": "e8dd8ca2-6fab-4acd-9b29-4e8583365d6d",
                "section_type": "main",
                "text": "Discussion\n\nRecent studies suggest inflammation to be an essential component of type 2 DM and its complications.We measured hs-CRP as a marker of inflammation in our diabetic cohort and found its levels to be significantly higher in diabetic patients as compared to controls and in nephropathy group as compared to diabetic subjects without nephropathy indicating inflammation to be a relevant factor in the pathogenesis of DN.Our results are consistent with an earlier study which has also reported increased hs-CRP levels in diabetics with proteinuria [18].Different inflammatory molecules, including pro-inflammatory cytokines have been proposed as critical factors in the development of microvascular diabetic complications, including nephropathy [19].It has been suggested that genetic variations in the genes encoding the inflammatory cytokines might confer susceptibility to DN by altering the function and/or expression of these cytokines.We investigated the association of genetic polymorphism(s) in inflammatory genes with the risk of diabetic nephropathy and whether co-occurrence of risk conferring variants of inflammatory genes were associated with increased risk of diabetic nephropathy in Asian Indian type 2 diabetic subjects.The key finding of our study was that polymorphisms in IL8, CCL2, CCR5, and MMP9 genes were associated with increased risk of nephropathy in Asian Indian type 2 diabetics and co-occurrence of specific risk genotypes of these genes conferred several fold greater risk of diabetic nephropathy."
            },
            {
                "document_id": "0951ba9d-bb8f-424b-b63f-16d94cb7166c",
                "section_type": "main",
                "text": "Page 43\n\nAuthor Manuscript\nAuthor Manuscript\nFig.  2 |.  Main signalling pathways that regulate cardiac remodelling in the diabetic heart.\n\n Author Manuscript\nAuthor Manuscript\n\nThe systemic glucotoxicity (as a result of increased production of advanced glycation end\nproducts (AGEs)), lipotoxicity and angiotensin II (Ang II) production associated with type 2\ndiabetes mellitus induce the generation of reactive oxygen species (ROS) and reactive\nnitrogen species (RNS) by endothelial cells, resulting in decreased nitric oxide (NO)\nbioavailability."
            },
            {
                "document_id": "c24330f7-9f82-404a-86d5-a16d814bb754",
                "section_type": "abstract",
                "text": "\nInsight into the molecular mechanisms that underlie the origin and progression of diabetic nephropathy remains limited in part because conventional research tools have restricted investigators to focus on single genes or isolated pathways.Microarray technologies provide opportunities for evaluating genetic factors and environmental effects at a genomic scale during the pathogenesis of diabetic nephropathy.Despite"
            },
            {
                "document_id": "230022b2-931e-42ab-b100-5e9776483d1a",
                "section_type": "main",
                "text": "Background:\n\nThe aim of this research was to investigate the retinal transcriptome changes in long-term streptozotocin (STZ)-induced rats' retinas using RNA sequencing (RNA-seq), to explore the molecular mechanisms of diabetic retinopathy (DR), and to identify novel targets for the treatment of DR by comparing the gene expression profile we obtained.Methods: In this study, 6 healthy male SD rats were randomly divided into wildtype (WT) group and streptozotocin (STZ)-induced group, 3 rats each group.After 6 months, 3 normal retina samples and 3 DM retina samples (2 retinas from the same rat were considered as 1 sample) were tested and differentially expressed genes (DEGs) were measured by RNA-seq technology.Then, we did Gene Ontology (GO) enrichment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and validated the results of RNA-seq through qRT-PCR.Results: A total of 118 DEGs were identified, of which 72 were up-regulated and 46 were down-regulated.The enriched GO terms showed that 3 most significant enrichment terms were binding (molecular function), cell part (cellular component), and biological regulation (biological process).The results of the KEGG pathway analysis revealed a significant enrichment in cell adhesion molecules, PI3K-Akt signaling pathway, and allograft rejection, etc. Conclusion: Our research has identified specific DEGs and also speculated their potential functions, which will provide novel targets to explore the molecular mechanisms of DR."
            },
            {
                "document_id": "7e809821-000d-4fff-971d-264650e3612b",
                "section_type": "main",
                "text": "Types of biomarkers include clinical, biochemical factors and molecular markers. Examples relevant to diabetic retinopathy include clinical factors (e.g.diabetes duration, obesity, smoking, ETDRS score, electroretinogram (ERGs) assessment; biochemical factors (e.g.HbA1c, lipoprotein related factors); and molecular factors (such as the results of GWAS analyses and miRNA profiles (discussed below).Cytokines, growth factors and/or hormones have been widely used, such as the case with adiponectin as an adipocyte-derived hormone that regulates glucose and lipid metabolism.Adiponectin has been shown to be significantly higher in T1D patients with severe diabetic retinopathy than in those without, even after adjustment for occurrence of microalbuminuria (Hadjadj et al., 2005).As retinopathy has multiple risk factors it is likely, as is increasingly used for cardiovascular disease and suggested for diabetic nephropathy (Elley et al., 2010;van Dieren et al., 2011;Vergouwe et al., 2010), and more recently for retinopathy (Harris Nwanyanwu et al., 2013)  from genetic data (Sandholm et al., 2012;Williams et al., 2012).In terms of genetic association the diabetic retinopathy field is less advanced than that for nephropathy, although there have been a number of worthwhile studies (reviewed by (Kuo et al., 2014)).A genome-wide association study for diabetic retinopathy identified an association with a long intergenic non-coding RNA (LincRNA) sequence.LincRNAs are non-protein coding transcripts (>200 nucleotides in length) and the sequence called RP1-90L14 (adjacent to the CEP162 gene) has shown susceptibility to diabetic retinopathy (Awata et al., 2014).Interestingly, other LincRNAs are also being studied for their association with diabetic retinopathy such as MALAT1 (Yan et al., 2014) and MIAT (Yan et al., 2015).While some interesting leads are emerging, as yet there is no robust indication that diabetic retinopathy has a significant genetic component.Candidate gene and genome-wide studies may yet find genetic linkage to particular retinopathy phenotypes in T1D and T2D although both diabetes-types will need to be assessed separately in view of their distinct genetic architecture."
            },
            {
                "document_id": "72aa5d47-336b-4e4f-8593-ee215b8891d2",
                "section_type": "main",
                "text": "\n\nWe hypothesize that the genes identified in our classification models (Table 5) represent products or 'genetic biomarkers' of the biological networks involved in diabetic neuropathy onset and progression.This idea is reinforced by the fact that several of the genes have known associations with diabetes or diabetic complications.We are particularly interested in CST1, whose expression was increased by 10-fold in progressors.CST1, encoding a cysteine protease inhibitor, was initially implicated in gastric and colorectal tumourigenesis (Choi et al., 2009;Yoneda et al., 2009).Another member of this protein family, cystatin C (CST3), has been identified as a prime predictor of diabetic nephropathy progression (Shimizu et al., 2003;Taglieri et al., 2009).Although the CST1 gene product has not been investigated in the context of diabetic complications, it is detectable in saliva, tears and urine (Choi et al., 2009).To date, there are no definitive biomarkers of diabetic neuropathy progression easily accessed from body fluids, and we speculate that CST1 could prove to be an easily measureable biomarker for diabetic neuropathy."
            },
            {
                "document_id": "e66846a6-1546-481b-baae-a55fc524c8af",
                "section_type": "main",
                "text": "In vivo relevance\n\nWhat is the evidence that these pathways are relevant in vivo?In rats with streptozotocin-induced diabetes, glomerular 12/15-LO mRNA and protein were upregulated 1, 2, 3, and 4 months after diabetes induction as demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) and by Western analysis and immunohistochemistry, respectively [14].Upstream of p38 MAPK is the signaling molecule MKK3/6, which is activated during the first 2 months in diabetic rats compared to controls [14].A similar pattern was observed for phospho-p38 MAPK and phospho-CREB.At 4 months, mesangial (and, parenthetically, podocyte) fibronectin accretion was increased; this phenomenon presumably contributes to mesangial expansion [14].I will loosely refer to this change as glomerulosclerosis.Thus, in diabetic rats, just as in mesangial cells and VSMCs in vitro, angiotensin II and high ambient glucose concentration activate a novel lipid-mediating signal transduction pathway, and in conjunction with MAPKs and transcription factors, lead to fibronectin synthesis; this process then accelerates renal disease."
            },
            {
                "document_id": "8f6c3be4-4598-4ae2-a7a8-8ea5a7a52794",
                "section_type": "main",
                "text": "Wnt signaling in diabetic nephropathy\n\nThe potential relevance of Wnt signaling in advanced DN was investigated in more detail.Mapping the respective genes found by each approach onto the canonical Wnt pathway was performed (KEGG [13] and Biocarta databases (BioCarta Pathways; http:// www.biocarta.com/genes/index.asp)).As shown in Fig. 4, and in line with previous findings, the CI-analysis identified a much larger fraction of the pathway as regulated than did the RMA analysis (23 versus 15 out of 27 genes, see Table S3 and Table S4).The potential downstream effects of this pathway on known Wnt target genes were then examined.Of the known Wnt target genes regulated on the microarray 15 of 15 were identified by CI while RMA identified 10 (Fig. 4 and Table S4).Matrix metalloproteinase 7 (MMP7) [14] showed the highest fold-change in Wnt-associated genes and was confirmed by RT-PCR on the cDNA used for the array analysis (DN 40.09623.88,LD: 1.061.73(p,0.05)) as well as on an independent cohort of patients with DN (DN: 6.4566.62;LD: 1.0060.79(p,0.05)) (Fig. 5a).The induction of MMP7 protein was verified by immunohistochemistry: MMP7 protein expression was strongly increased in the tubulo-interstitial compartment of patients with DN (Fig. 2 and Fig. 5b,c)"
            },
            {
                "document_id": "42e06cda-627e-46f2-a289-c4c1fb6af8f2",
                "section_type": "main",
                "text": "\n\nIn the past, many scientific studies were focused on ED in type 1 DM (Chitaley et al. 2009).However, there are more complicated but less comprehensive mechanisms in T2DMED (Chitaley 2009).The potential underlying mechanisms include hypogonadism, vascular dysfunction, veno-occlusive disorders, and others (Hidalgo-Tamola and Chitaley 2009).Some mechanisms, such as non-adrenergic and non-cholinergic dysfunction, are still debated in the pathogenesis of T2DMED (Chitaley et al. 2009).To our knowledge, only a few studies regarding of miRNA expression or function in DMED have been reported.Recently, miRNA expression was investigated in a murine model with vasculogenic ED induced by a long-term high fat diet (Barbery et al. 2015).Though accompanied with impaired glucose tolerance, this animal model could not fully represent the pathogenic processes of DMED.Instead, a classical genetic modified murine model with T2DMED was used in the present study, to investigate differentially expressed microRNAs.The bioinformatic analyses of differentially expressed miRNAs were further performed to detect whether these miRNAs played potential roles in the mechanisms of T2DMED."
            },
            {
                "document_id": "34184c8d-b167-4ae8-bfce-01e18d78fe41",
                "section_type": "abstract",
                "text": "\nGenetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression.The address for the corresponding author was captured as affiliation for all authors.Please check if appropriate.Gene(2017),"
            }
        ],
        "document_id": "7A3E5866E55FB9764BF9F70CFF63A333",
        "engine": "gpt-4",
        "first_load": false,
        "focus": "api",
        "keywords": [
            "diabetes",
            "microRNAs",
            "lncRNAs",
            "diabetic&nephropathy",
            "diabetic&retinopathy",
            "TGF-β1",
            "angiogenesis",
            "fibrosis",
            "inflammation",
            "hyperglycemia"
        ],
        "metadata": [
            {
                "object": "in this review, we focus on two microRNAs centrally involved in lung cancer progression. MicroRNA-21 promotes and microRNA-34 inhibits cancer progression. We elucidate here involved pathways and imbed these antagonistic microRNAs in a network of interactions, stressing their cancer microRNA biology, followed by experimental and bioinformatics analysis of such microRNAs and their targets",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab403726"
            },
            {
                "object": "The present study shows that elevated plasma levels of RBP4 were associated with diabetic retinopathy and vision-threatening diabetic retinopathy in Chinese patients with type 2 diabetes, suggesting a possible role of RBP4 in the pathogenesis of diabetic retinopathy complications. Lowering RBP4 could be a new strategy for treating type 2 diabetes with diabetic retinopathy .",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab851311"
            },
            {
                "object": "Reporter assays reveal regulation by microRNA-339, microRNA-556, and, to a lesser extent, microRNA-10 and microRNA-199. MicroRNA-339 and microRNA-556 were further found to directly decrease Klotho protein expression in aging tissue.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab642566"
            },
            {
                "object": "after orthotopic lung transplantation, in the IL-17A KO group, less inflammation in the bronchovascular axis was observed and a non-significant trend towards less bronchovascular fibrosis, pleural/septal inflammation and fibrosis, and parenchymal inflammation and fibrosis when compared to WT mice",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab49527"
            },
            {
                "object": "*TFEB overexpression inhibits vascular inflammation in diabetic db/db mice. TFEB overexpression inhibits vascular inflammation in diabetic db/db mice .TFEB suppresses IKK activity to protect IkappaBalpha from degradation, thereby, inhibiting NF-kappaB p65 nuclear localization and attenuating vascular inflammation in endothelial cells of these mice.  laminar shear stress induces TFEB through KLF2 which activates its pro...",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab7633"
            },
            {
                "object": "Data suggest that urine AQP5/creatinine ratio is significantly higher in patients with diabetic nephropathy than in control subjects, subjects diabetes, or subjects with nephropathy of unknown etiology; urine AQP5/creatinine ratio increases with stage of diabetic nephropathy; this biomarker may improve clinical models in distinguishing diabetic nephropathy from normal controls and subjects with type 2 diabetic alone.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab213643"
            },
            {
                "object": "Angiogenesis and hepatic fibrosis are mutually stimulatory, such that fibrosis requires angiogenesis and angiogenesis requires angiopoietin 1 from activated HSCs.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab72845"
            },
            {
                "object": "MicroRNA-625-3p was highly expressed in oral squamous cell carcinoma OSCC tissues. OSCC patients with T3+T4 stage had higher expression of microRNA-625-3p than those with T1+T2 stage. SCAI was identified as a target gene of microRNA-625-3p. ROC curve showed that microRNA-625-3p and SCAI exert certain values in diagnosing OSCC. MicroRNA-625-3p promoted migration of OSCC cells, which was reversed by SCAI knockdown.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab483708"
            },
            {
                "object": "Angiogenesis and hepatic fibrosis are mutually stimulatory, such that fibrosis requires angiogenesis and angiogenesis requires angiopoietin 1 from activated HSCs.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab72844"
            },
            {
                "object": "Hyperglycemia could induce pathological angiogenesis in subcutaneous Matrigel of diabetic rats, and Ang-1 could upregulate the expression of intercellular junction protein in subcutaneous Matrigel of diabetic rats and promote the integrity of neovascularization in the subcutaneous Matrigel of diabetic rats",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab367213"
            }
        ],
        "question": "What non-coding RNAs are involved in diabetes, and what roles do they play?",
        "subquestions": null,
        "task_id": "7A3E5866E55FB9764BF9F70CFF63A333",
        "usage": {
            "chatgpt": 13184,
            "gpt-4": 7924,
            "gpt-4-turbo-preview": 6969
        },
        "user_id": 2
    },
    "document_id": "7A3E5866E55FB9764BF9F70CFF63A333",
    "task_id": "7A3E5866E55FB9764BF9F70CFF63A333"
}