Therapeutic potential of urine exosomes derived from rats with diabetic kidney disease.

Kidney disease is prevalent in diabetes. Urinary exosomes (uE) from animal models and patients with Diabetic nephropathy (DN) showed increased levels of miRs with reno-protective potential. We examined whether urinary loss of such miRs is associated with their reduced renal levels in DN patients. We also tested whether injecting uE can leverage kidney disease in rats. In this study (study-1) we performed microarray profiling of miRNA in uE and renal tissues in DN patients and subjects with diabetes without DN (controls). In study-2, diabetes was induced in Wistar rats by Streptozotocin (i.p. 50 mg/kg of body weight). Urinary exosomes were collected at 6th, 7th and 8th weeks, and injected back into the rats (100ug/biweekly, uE-treated n=7) via tail vein on weeks 9 and 10. Equal volume of vehicle was injected in controls (vehicle, n=7). uE from the human and rat showed the presence of exosome-specific proteins by immunoblotting. Microarray profiling revealed a set of 15 miRs having high levels in the uE, while lower in renal biopsies, from DN, compared to controls (n=5-9/group). Bioinformatic analysis also confirmed the Renoprotective potential of these miRs. Taqman qPCR confirmed the opposite regulation of miR-200c-3p and miR-24-3p in paired uE and renal biopsy samples from DN patients (n=15), relative to non-DN controls. A rise in 28 miRs levels, including miR-200c-3p, miR-24-3p, miR-30a-3p and miR-23a-3p were observed in the uE of DN rats, collected between 6th-8th weeks, relative to baseline (before diabetes induction). uE- treated DN rats had significantly reduced urine albumin-to-creatinine ratio, attenuated renal pathology, and lower miR-24-3p target fibrotic/inflammatory genes (TGF-beta, and Collagen IV), relative to vehicle treated DN rats. In uE treated rats, the renal expression of miR-24-3p, miR-30a-3p, let-7a-5p and miR-23a-3p was increased, relative to vehicle control. Patients with diabetic nephropathy had reduced renal levels, while higher uE abundance of miRs with reno-protective potential. Reverting the urinary loss of miRs by injecting uE attenuated renal pathology in diabetic rats.

A Path-Following Controller for Marine Vehicles Using a Two-Scale Inner-Outer Loop Approach.

This article addresses the problem of path following of marine vehicles along straight lines in the presence of currents by resorting to an inner-outer control loop strategy, with due account for the presence of currents. The inner-outer loop control structures exhibit a fast-slow temporal scale separation that yields simple "rules of thumb" for controller tuning. Stated intuitively, the inner-loop dynamics should be much faster than those of the outer loop. Conceptually, the procedure described has three key advantages: (i) it decouples the design of the inner and outer control loops, (ii) the structure of the outer-loop controller does not require exact knowledge of the vehicle dynamics, and (iii) it provides practitioners a very convenient method to effectively implement path-following controllers on a wide range of vehicles. The path-following controller discussed in this article is designed at the kinematic outer loop that commands the inner loop with the desired heading angles while the vehicle moves at an approximately constant speed. The key underlying idea is to provide a seamless implementation of path-following control algorithms on heterogeneous vehicles, which are often equipped with heading autopilots. To this end, we assume that the heading control system is characterized in terms of an IOS-like relationship without detailed knowledge of vehicle dynamics parameters. This paper quantitatively evaluates the combined inner-outer loop to obtain a relationship for assessing the combined system's stability. The methods used are based on nonlinear control theory, wherein the cascade and feedback systems of interest are characterized in terms of their IOS properties. We use the IOS small-gain theorem to obtain quantitative relationships for controller tuning that are applicable to a broad range of marine vehicles. Tests with AUVs and one ASV in real-life conditions have shown the efficacy of the path-following control structure developed.

An In-Silico Approach to Identify Therapeutic Target and Markers Associated with Diabetic Nephropathy.

BACKGROUND: Renal disease in T2DM could arise independent of hyperglycemia, aka non diabetic kidney disease. Their prevalence ranges from 33%to72.5% among T2DM patients. Specific molecular signatures that distinguish Diabetic Nephropathy from NDKD (FSGS) in T2DM might provide new targets for CKD management. METHODS: Five original GEO microarray DN and FSGS datasets were evaluated (GSE111154, GSE96804, GSE125779, GSE129973 and GSE121233). Each of the three groups (DN, FSGS, and Controls) had equal renal transcriptome data (n=32) included in the analysis to eliminate bias. The DEGs were identified using TAC4.0. Pathway analysis was performed on the discovered genes that aligned to official gene symbols using Reactome, followed by functional gene enrichment analysis using Funrich,Enrichr. STRING and Network analyst investigated PPI, followed by Webgestalt's pathway enrichment. Finally, using the Targetscan7.0 and DIANA tools, filtered differential microRNAs downregulated in DN were evaluated for target identification. RESULT: Between the three groups, DN, FSGS, and Control, a total of 194 DEGs. with foldchange >2&<-2 and P-value0.01 were found in the renal transcriptome. In comparison to control, 45 genes were elevated particularly in DN, whereas 43 were upregulated specifically in FSGS. DN datasets were compared to FSGS in a separate analysis. FABP4, EBF1, ADIRF, and ART4 were shown to be among the substantially up-regulated genes unique to DN in both analyses. The transcriptional regulation of white adipocytes was discovered by a pathway analysis. CONCLUSION: The molecular markers revealed might be employed as specific targets in the aetiology of DN, as well as in T2DM patients' therapeutic care.

Interaction network analysis of YBX1 for identification of therapeutic targets in adenocarcinomas.

Human Y-box binding protein-1 (YBX1) is a member of highly conserved cold-shock domain protein family, which is involved in transcriptional as well as translational regulation of many genes. Nuclear localization of YBX1 has been observed in various cancer types and it's overexpression has been linked to adverse clinical outcome and poor therapy response, but no diagnostic or therapeutic correlation has been established so far. This study aimed to identify differentially expressed novel genes among the interactors of YBX1 in different cancer types. Analysis of RNA-Seq data for colorectal, lung, prostate and stomach adenocarcinoma identified 39 unique genes, which are differentially expressed in the four adenocarcinoma types. Gene-enrichment analysis for the differentially expressed genes from individual adenocarcinoma with focus on unique genes resulted in a total of 57 gene sets specific to each adenocarcinoma. Gene ontology for commonly expressed genes suggested the pathways and possible mechanisms through which they affect each adenocarcinoma type considered in the study. Gene regulatory network constructed for the common genes and network topology was analyzed for the central nodes. Here 12 genes were found to play important roles in the network formation; among them, two genes FOXM1 and TOP2A were found to be in central network formation, which makes them a common target for therapeutics. Furthermore, five common differentially expressed genes in all adenocarcinomas were also identified.

Expression and network analysis of YBX1 interactors for identification of new drug targets in lung adenocarcinoma.

Y-Box Binding protein 1 (YBX-1) is known to be involved in various types of cancers. It's interactors also play major role in various cellular functions. Present work aimed to study the expression profile of the YBX-1 interactors during lung adenocarcinoma (LUAD). The differential expression analysis involved 57 genes from 95 lung adenocarcinoma samples, construction of gene network and topology analysis. A Total of 43 genes were found to be differentially expressed from which 17 genes were found to be down regulated and 26 genes were up-regulated. We observed that Polyadenylate-binding protein 1 (PABPC1), a protein involved in YBX1 translation, is highly correlated with YBX1. The interaction network analysis for a differentially expressed non-coding RNA Growth Arrest Specific 5 (GAS5) suggests that two proteins namely, Growth Arrest Specific 2 (GAS2) and Peripheral myelin protein 22 (PMP22) are potentially involved in LUAD progression. The network analysis and differential expression suggests that Collagen type 1 alpha 2 (COL1A2) can be potential biomarker and target for LUAD.

Comparative genomic analysis of Rickettsia rickettsii for identification of drug and vaccine targets: tolC as a proposed candidate for case study.

BACKGROUND: Antibiotic resistance is increasing rapidly in pathogenic organisms, creating more complications for treatment of diseases. Rocky Mountain spotted fever (RMSF) is a neglected tropical disease in humans caused by Rickettsia rickettsii for which no effective therapeutic is available. Subtractive genomics methods facilitate the characterization of non-homologous essential proteins that could be targeted for the discovery of potential therapeutic compounds against R. rickettsii to combat RMSF. Present study followed an in-silico based methodology, involving scanning and filtering the complete proteome of Rickettsia rickettsii by using several prioritization parameters in the search of potential candidates for drug development. Further the putative targets were subjected to series of molecular dockings with ligands obtained from PDB ligand database to identify suitable potential inhibitors. The comparative genomic analysis revealed 606 non-homologous proteins and 233 essential non-homologous proteins of R. rickettsii. The metabolic pathway analysis predicted 120 proteins as putative drug targets, out of which 56 proteins were found to be associated with metabolic pathways unique to the bacteria and further subcellular localization analysis revealed that 9 proteins as potential drug targets which are secretion proteins, involved in peptidoglycan biosynthesis, folate biosynthesis and bacterial secretion system. As secretion proteins are more feasible as vaccine candidates, we have selected a most potential target i.e. tolC, an outer membrane efflux protein that belongs to type I secretion system and has major role in pathogen survival as well as MDR persistence. So for case study, we have modelled the three dimensional structure of tolC (tunnel protein). The model was further subjected to virtual screening and in-silico docking. The study identified three potential inhibitors having PDB Id 19V, 6Q8 and 39H. Further we have suggested that the above study would be most important while considering the selection of candidate targets and drug or vaccine designing against R. rickettsii.

Docking-based Screening of Ficus religiosa Phytochemicals as Inhibitors of Human Histamine H2 Receptor.

BACKGROUND: Ficus religiosa L. is generally known as Peepal and belongs to family Moraceae. The tree is a source of many compounds having high medicinal value. In gastrointestinal tract, histamine H2 receptors have key role in histamine-stimulated gastric acid secretion. Their over stimulation causes its excessive production which is responsible for gastric ulcer. OBJECTIVE: This study aims to screen the range of phytochemicals present in F. religiosa for binding with human histamine H2 and identify therapeutics for a gastric ulcer from the plant. MATERIALS AND METHODS: In this work, a 3D-structure of human histamine H2 receptor was modeled by using homology modeling and the predicted model was validated using PROCHECK. Docking studies were also performed to assess binding affinities between modeled receptor and 34 compounds. Molecular dynamics simulations were done to identify most stable receptor-ligand complexes. Absorption, distribution, metabolism, excretion, and screening was done to evaluate pharmacokinetic properties of compounds. RESULTS: The results suggest that seven ligands, namely, germacrene, bergaptol, lanosterol, Ergost-5-en-3beta-ol, α-amyrin acetate, bergapten, and γ-cadinene showed better binding affinities. CONCLUSION: Among seven phytochemicals, lanosterol and α-amyrin acetate were found to have greater stability during simulation studies. These two compounds may be a suitable therapeutic agent against histamine H2 receptor. SUMMARY: This study was performed to screen antiulcer compounds from F. religiosa. Molecular modeling, molecular docking and MD simulation studies were performed with selected phytochemicals from F. religiosa. The analysis suggests that Lanosterol and α-amyrin may be a suitable therapeutic agent against histamine H2 receptor. This study facilitates initiation of the herbal drug discovery process for the antiulcer activity. Abbreviations used: ADMET: Absorption, distribution, metabolism, excretion and toxicity, DOPE: Discrete Optimized Potential Energy, OPLS: Optimized potential for liquid simulations, RMSD: Root-mean-square deviation, HOA: Human oral absorption, MW: Molecular weight, SP: Standard-precision, XP: Extra-precision, GPCRs: G protein-coupled receptors, SASA: Solvent accessible surface area, Rg: Radius of gyration, NHB: Number of hydrogen bond.

Role of Y Box Protein-1 in cancer: As potential biomarker and novel therapeutic target.

The Y-box binding protein (YB-1) is known to be a multifunctional transcription and translation factor during expression of several proteins. It is a vital oncoprotein that regulates cancer cell progression and proliferation. YB-1 is over-expressed in various human cancers such as breast cancer, colon cancer, lung cancer, gastric cancer, oesophageal cancer and glioblastoma. Nuclear expression of YB-1 is found to be associated with multidrug resistance and cancer cell progression. YB-1 is reported to regulate many cellular signalling pathways in different types of cancer proliferation. Knowledge about nuclear localization and nuclear level expression of YB-1 in different cancers has been correlated with prospective prognosis of cancer. This review discusses the prospects of YB-1 as a potential biomarker as well as therapeutic target in lieu of their role during cancer progression and multidrug resistance.

Stability and mobility of vacancy-H complexes in Al.

The effect of hydrogen loading on the stability and mobility of vacancy-H complexes in aluminum is determined by applying DFT and the minimum-mode-following method. The binding energy per H-atom within a complex is found to range from -0.36 eV/atom to -0.34 eV/atom for an occupancy of, respectively, a single and eight H-atoms. When eight H-atoms are neighboring the vacancy the total binding energy becomes -2.72 eV. However, already at a load level of two H-atoms the total binding energy reaches -0.70 eV, which fully compensates the vacancy creation energy. It is observed that for complexes with four or more H-atoms the vacancy gets pinned, as the diffusion barrier increases by a factor of two, reaching a value of 1.03 eV or more. The explanation for the increased energy barrier is that at the higher hydrogen load levels the system must traverse an energetically unfavorable configuration where two or more H-atoms are separated from the vacancy. As a possible consequence of the decreased mobility and increased stability, highly loaded vacancy-H complexes are likely to act as nucleation sites for extended defects.