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Due to the differences between the storage mode of relational database and graph database,during the process of transforming data in relational database to graph database,it is necessary to solve the main problems of edge definition,vertex uniqueness and retention of original database constraint information.To solve the above problems,a method of transforming relational database to graph database is proposed.Firstly,by customizing the existing primary key,combined with the uniqueness of the table name,the problem of ensuring the uniqueness of the vertex is solved;through different configuration schemes,the constraint information of the original relational database can be maximized.Then,the edge definition method based on configuration and intermediate table (EDCIT) method is proposed,it provides different edge mapping solutions for multiple types of databases and solves the definition of edges during the transformation.Finally,through experiments on multiple data sets,and using Gremlin statement to test the transformed data,it verifies the integrity and reliability of the transformed data.

Background & objectives: The present study proposed a series of computational techniques such as homology modelling, molecular simulation, and molecular docking to be performed to explore the structural features and binding mechanism of Cytochrome c oxidase subunit I (COX1) protein with known inhibitors. Methods: Elucidation of the three-dimensional structure of COX1 protein was carried out by using MODELLER software. The modelled protein was validated using GROMACS, structural qualitative tools and web servers. Finally the model was docked with carbon monoxide (CO) and nitric oxide (NO) using Auto Dock Tools. Results: The three-dimensional structure of mitochondrial transmembrane protein COX1 was built using homology modelling based on high-resolution crystal structures of Bos taurus. Followed by inserting the lipid bilayer, molecular dynamics simulation was performed on the modelled protein structure. The modelled protein was validated using qualitative structural indices. Known inhibitors such as carbon monoxide (CO) and nitric oxide (NO) inhibit their active binding sites of mitochondrial COX1 and the inhibitors were docked into the active site of attained model. A structure-based virtual screening was performed on the basis of the active site inhibition with best scoring hits. The COX1 model was submitted and can be accessible from the Model Archive site through the following link https://www.modelarchive.org/doi/10.5452/ma-at44v. Interpretation & conclusion: Structural characterization and active site identification can be further used as target for the planning of potent mosquitocidal compounds, thereby assisting the information in the field of research.

Kako smo unatrag nekoliko godina dobili određena sredstva (tzv. sveučilišne potpore) kojima smo istraživali određene aspekte grafovskih baza podataka, odlučili smo rezultate istraživanja predstaviti i hrvatskoj akademskoj i stručnoj zajednici. Smatramo kako su istraživanja bila kvalitetna i da rezultati istih imaju potencijal za širu primjenu i implementaciju u dostupnim sustavima za upravljanje grafovskim bazama podataka. Također, postoje i određene mogućnosti za proširenje implementiranih rješenja, kao i prostor za dodatna istraživanja i preslikavanja relacijskih u koncepte grafovskih baza podataka.

Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treatment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provides limited efficacy and an important burden of adverse events. Epigenetic drugs are a source of novel therapeutic tools. Among them, bromodomain and extraterminal domain (BET) inhibitors (iBETs) block the interaction between bromodomains and acetylated proteins, including histones and transcription factors. iBETs have demonstrated protective effects on malignancy, inflammatory disorders and experimental kidney disease. Recently, Gremlin-1 was proposed as a urinary biomarker of disease progression in human anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. We have now evaluated whether iBETs could regulate Gremlin-1 in experimental anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS) in mice, a model resembling human crescentic glomerulonephritis. In NTS-injected mice, the iBET JQ1 inhibited renal Gremlin-1 overexpression and diminished glomerular damage, restoring podocyte numbers. Chromatin immunoprecipitation assay demonstrated BRD4 enrichment of the Grem-1 gene promoter in injured kidneys, consistent with Gremlin-1 epigenetic regulation. Moreover, JQ1 blocked BRD4 binding and inhibited Grem-1 gene transcription. The beneficial effect of iBETs was also mediated by modulation of NOTCH pathway. JQ1 inhibited the gene expression of the NOTCH effectors Hes-1 and Hey-1 in NTS-injured kidneys. Our results further support the role for epigenetic drugs, such as iBETs, in the treatment of rapidly progressive crescentic glomerulonephritis.

Chronic kidney disease (CKD) is emerging as an important health problem due to the increase number of CKD patients and the absence of an effective curative treatment. Gremlin has been proposed as a novel therapeutic target for renal inflammatory diseases, acting via Vascular Endothelial Growth Factor Receptor-2 (VEGFR2). Although many evidences suggest that Gremlin could regulate renal fibrosis, the receptor involved has not been yet clarified. Gremlin, as other TGF-β superfamily members, regulates tubular epithelial to mesenchymal transition (EMT) and, therefore, could contribute to renal fibrosis. In cultured tubular epithelial cells Gremlin binding to VEGFR2 is linked to proinflammatory responses. Now, we have found out that in these cells VEGFR2 is also involved in the profibrotic actions of Gremlin. VEGFR2 blockade by a pharmacological kinase inhibitor or gene silencing diminished Gremlin-mediated gene upregulation of profibrotic factors and restored changes in EMT-related genes. Moreover, VEGFR2 inhibition blocked EMT phenotypic changes and dampened the rate of wound healing in response to Gremlin. The role of VEGFR2 in experimental fibrosis was evaluated in experimental unilateral ureteral obstruction. VEFGR2 inhibition diminished the upregulation of profibrotic genes and EMT changes, as well as the accumulation of extracellular matrix proteins, such as fibronectin and collagens in the obstructed kidneys. Notch pathway activation participates in renal damage progression by regulating cell growth/proliferation, regeneration and inflammation. In cultured tubular epithelial cells, Notch inhibition markedly downregulated Gremlin-induced EMT changes and wound healing speed. These results show that Gremlin regulates the EMT process via VEGFR2 and Notch pathway activation, suggesting that the Gremlin/VEGFR2 axis could be a potential therapeutic target for CKD.

En enfermedad renal crónica (ERC) el riesgo aumentado de muerte por causa cardiovascular se relaciona con calcificaciones vasculares precoces y progresivas. Estas calcificaciones ocurren por un proceso altamente regulado. En los vasos de los pacientes con ERC coexisten calcificaciones en la íntima vascular asociadas a ateroesclerosis, pero además hay calcificaciones en la túnica media del vaso. Estos dos tipos de calcificaciones tienen distintas consecuencias fisiopatológicas cardiovasculares. Los principales componentes que interactúan para producir calcificación de la matriz extracelular son la célula muscular lisa vascular (CMLV), factores que inician el proceso de transformación osteocondrogénica, inductores e inhibidores de la calcificación, factores que regulan a estos últimos. Como respuesta al proceso de calcificación, el vaso expresa inhibidores que disminuyen la diferenciación osteoblástica, amplificando la lesión ósea adinámica. Así, el conocimiento del proceso patológico bidireccional del eje Hueso-Vaso ayuda a explicar la estrecha correlación entre pérdida de masa ósea y calcificación vascular.

Of the circa 40 cytokines of the TGF-β superfamily, around a third are currently known to bind to heparin and heparan sulphate. This includes TGF-β1, TGF-β2, certain bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), as well as GDNF and two of its close homologues. Experimental studies of their heparin/HS binding sites reveal a diversity of locations around the shared cystine-knot protein fold. The activities of the TGF-β cytokines in controlling proliferation, differentiation and survival in a range of cell types are in part regulated by a number of specific, secreted BMP antagonist proteins. These vary in structure but seven belong to the CAN or DAN family, which shares the TGF-β type cystine-knot domain. Other antagonists are more distant members of the TGF-β superfamily. It is emerging that the majority, but not all, of the antagonists are also heparin binding proteins. Any future exploitation of the TGF-β cytokines in the therapy of chronic diseases will need to fully consider their interactions with glycosaminoglycans and the implications of this in terms of their bioavailability and biological activity.

Abstract Background Gremlin, a bone morphogenetic protein antagonist, plays an important role in the pathogenesis of diabetic nephropathy (DN). However, the specific molecular mechanism underlying Gremlin’s involvement in DN has not been fully elucidated. In the present study, we investigated the role of Gremlin on cell proliferation and accumulation of extracellular matrix (ECM) in mouse mesangial cells (MMCs), and explored the relationship between Gremlin and the ERK1/2 pathway. Methods To determine expression of Gremlin in MMCs after high glucose (HG) exposure, Gremlin mRNA and protein expression were evaluated using real-time polymerase chain reaction and western blot analysis, respectively. To determine the role of Gremlin on cell proliferation and accumulation of ECM, western blot analysis was used to assess expression of pERK1/2, transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF). Cell proliferation was examined by bromodeoxyuridine (BrdU) ELISA, and accumulation of collagen IV was measured using a radioimmunoassay. This enabled the relationship between Gremlin and ERK1/2 pathway activation to be investigated. Results HG exposure induced expression of Gremlin, which peaked 12 h after HG exposure. HG exposure alone or transfection of normal-glucose (NG) exposed MMCs with Gremlin plasmid (NG + P) increased cell proliferation. Transfection with Gremlin plasmid into MMCs previously exposed to HG (HG + P) significantly increased this HG-induced phenomenon. HG and NG + P conditions up-regulated protein levels of TGF-β1, CTGF and collagen IV accumulation, while HG + P significantly increased levels of these further. Inhibition of Gremlin with Gremlin siRNA plasmid reversed the HG-induced phenomena. These data indicate that Gremlin can induce cell proliferation and accumulation of ECM in MMCs. HG also induced the activation of the ERK1/2 pathway, which peaked 24 h after HG exposure. HG and NG + P conditions induced overexpression of pERK1/2, whilst HG + P significantly induced levels further. Inhibition of Gremlin by Gremlin siRNA plasmid reversed the HG-induced phenomena. This indicates Gremlin can induce activation of the ERK1/2 pathway in MMCs. Conclusion Culture of MMCs in the presence of HG up-regulates expression of Gremlin. Gremlin induces cell proliferation and accumulation of ECM in MMCs. and enhances activation of the ERK1/2 pathway.

Abstract Background The possible role of secretory products of fibrous tissue in the development of hepatocellular carcinoma (HCC) complicating chronic hepatitis C was investigated. Our hypothesis was that gremlin, secreted by fibroblasts, inhibited bone morphogenic protein (BMP), which mediates stem cell maturation into adult functioning hepatocytes, and thus, arrest stem cell maturation and promoted their proliferation in an immature state possibly culminating into development of HCCs. Results Protein expression of cytokeratin 19 (CK19) and fibroblast growth factor 2 (FGF-2), and mRNA expression of gremlin and BMP-7 were studied in 35 cases of chronic hepatitis, cirrhosis and HCC complicating chronic hepatitis C. CK19 expression was higher in cases of cirrhosis (0.004), which correlated with the grade (r = 0.64, p = 0.009) and stage (r = 0.71, p = 0.001). All HCCs were negative for CK19. Stem cell niche activation (as indicated as a ductular reaction) was highest in cases of cirrhosis (p = 0.001) and correlated with CK19 expression (r = 0.42, p = 0.012), the grade(r = 0.56, p = 0.024) and stage (0.66, p = 0.006). FGF-2 expression was highest in HCCs and correlated with the grade (r = 0.6, p = 0.013), stage (0.72, p = 0.002), CK19 expression (r = 0.71, p = 002) and ductular reaction (0.68, p = 0.004) in hepatitis cases. Higher numbers of cirrhosis cases and HCCs (p = 0.009) showed gremlin expression, which correlated with the stage (r = 0.7, p = 0.002). Gremlin expression correlated with that of CK19 (r = 0.699, p = 0.003) and FGF2 (r = 0.75, p = 0.001) in hepatitis cases. Conclusions Fibrosis promotes carcinogenesis by fibroblast-secreted gremlin that blocks BMP function and promotes stem cell activation and proliferation as well as possibly HCC development.