Astragalus Polysaccharide Ameliorates Renal Inflammatory Responses in a Diabetic Nephropathy by Suppressing the TLR4/NF-κB Pathway.

Background: Diabetic nephropathy (DN), as a chronic inflammatory complication of diabetes, is characterized by hyperglycemia, albuminuria and edema, which ultimately becomes the leading cause of end-stage renal disease (ESRD). Astragalus polysaccharide (APS), extracted from the Astragalus membranaceus, was widely used in the treatment of diabetes mellitus. However, the functional roles of APS ameliorate inflammatory responses in DN, which remain poorly understood. Therefore, the purpose of this study was to explore the molecular mechanism of APS on DN in vivo and vitro models. Methods: We explored the beneficial effects of APS in streptozotocin (STZ)-induced DN rat model and high glucose (HG)-treated glomerular podocyte model. The fasting blood glucose (FBG) and ratio of kidney weight to body weight were measured after 4 weeks of APS treatment. The renal injury parameters containing serum creatinine (Scr), blood urea nitrogen (BUN) and 24 h urinary protein were evaluated. The renal pathological examination was observed by hematoxylin-eosin (HE) staining. The levels of IL-1ß, IL-6 and MCP-1 were evaluated by ELISA assay. The proliferation of podocytes was determined using CCK-8 assay and flow cytometry. qRT-PCR and Western blot analysis were performed to determine the amounts of TLR4/NF-κB-related gene expression. Results: Our results indicated that APS effectively decreased the levels of FBG, BUN, Scr and renal pathological damage when compared with STZ-induced DN model group. Additionally, APS significantly ameliorated renal injury by reducing inflammatory cytokines IL-1ß, IL-6, MCP-1 expression and inhibiting the TLR4/NF-κB pathway activity in DN rats. Consistent with the results in vitro, the HG-induced inflammatory response and proliferation of glomerular podocytes were also alleviated through APS administration. Conclusion: We found that APS ameliorated DN renal injury, and the mechanisms perhaps related to relieving inflammatory responses and attenuating the TLR4/NF-κB signaling pathway.

Modeling of Fiber-Constrained Planar PVC Gel Actuators.

In recent years, plasticized poly (vinyl chloride) (PVC) gel has attracted increasing attention in soft robotics. However, there is scarce research on the deformation mechanism and modeling of PVC gel actuators. In this study, to investigate the deformation mechanism of fiber-constrained planar PVC gel actuators, we propose a complex nonlinear model based on traditional thermodynamic electroactive polymer (EAP) multi-field coupling theory. The proposed model can reveal the dielectric breakdown strength of PVC gels and predict the deformation of planar PVC gel actuators with varying levels of pre-stretching. The theoretical results were in good agreement with the experimental results, indicating the feasibility of the proposed model.

Comprehensive analysis of m6A modification lncRNAs in high glucose and TNF-α induced human umbilical vein endothelial cells.

N6-methyladenosine (m6A) RNA methylation, as a reversible epigenetic modification of mammalian mRNA, holds a critical role in multiple biological processes. m6A modification in Long non-coding RNAs (lncRNAs) has increasingly attracted more attention in recent years, especially in diabetics, with or without metabolic syndrome. We investigated via m6A-sequencing and RNA-sequencing the differentially expressed m6A modification lncRNAs by high glucose and TNF-α induced endothelial cell dysfunction in human umbilical vein endothelial cells. Additionally, gene ontology and kyoto encyclopedia of genes and genomes analyses were performed to analyze the biological functions and pathways for the target of mRNAs. Lastly, a competing endogenous RNA network was established to further reveal a regulatory relationship between lncRNAs, miRNAs and mRNAs. A total of 754 differentially m6A-methylated lncRNAs were identified, including 168 up-regulated lncRNAs and 266 down-regulated lncRNAs. Then, 119 significantly different lncRNAs were screened out, of which 60 hypermethylated lncRNAs and 59 hypomethylated lncRNAs. Moreover, 122 differentially expressed lncRNAs were filtered, containing 14 up-regulated mRNAs and 18 down-regulated lncRNAs. Gene ontology and kyoto encyclopedia of genes and genomes analyses analyses revealed these targets were mainly associated with metabolic process, HIF-1 signaling pathway, and other biological processes. The competing endogenous RNA network revealed the regulatory relationship between lncRNAs, miRNAs and mRNAs, providing potential targets for the treatment and prevention of diabetic endothelial cell dysfunction. This comprehensive analysis for lncRNAs m6A modification in high glucose and TNF-α-induced human umbilical vein endothelial cells not only demonstrated the understanding of characteristics of endothelial cell dysfunction, but also provided the new targets for the clinical treatment of diabetes. Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval will not be required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences.

Bioinformatics Analysis of the Mechanisms of Diabetic Nephropathy via Novel Biomarkers and Competing Endogenous RNA Network.

Diabetic nephropathy (DN) is one of the common chronic complications of diabetes with unclear molecular mechanisms, which is associated with end-stage renal disease (ESRD) and chronic kidney disease (CKD). Our study intended to construct a competing endogenous RNA (ceRNA) network via bioinformatics analysis to determine the potential molecular mechanisms of DN pathogenesis. The microarray datasets (GSE30122 and GSE30529) were downloaded from the Gene Expression Omnibus database to find differentially expressed genes (DEGs). GSE51674 and GSE155188 datasets were used to identified the differentially expressed microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), respectively. The DEGs between normal and DN renal tissues were performed using the Linear Models for Microarray (limma) package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to reveal the mechanisms of DEGs in the progression of DN. The protein-protein interactions (PPI) of DEGs were carried out by STRING database. The lncRNA-miRNA-messenger RNA (mRNA) ceRNA network was constructed and visualized via Cytoscape on the basis of the interaction generated through the miRDB and TargetScan databases. A total of 94 significantly upregulated and 14 downregulated mRNAs, 31 upregulated and 121 downregulated miRNAs, and nine upregulated and 81 downregulated lncRNAs were identified. GO and KEGG pathways enriched in several functions and expression pathways, such as inflammatory response, immune response, identical protein binding, nuclear factor kappa b (NF-κB) signaling pathway, and PI3K-Akt signaling pathway. Based on the analysis of the ceRNA network, five differentially expressed lncRNAs (DElncRNAs) (SNHG6, KCNMB2-AS1, LINC00520, DANCR, and PCAT6), five DEmiRNAs (miR-130b-5p, miR-326, miR-374a-3p, miR-577, and miR-944), and five DEmRNAs (PTPRC, CD53, IRF8, IL10RA, and LAPTM5) were demonstrated to be related to the pathogenesis of DN. The hub genes were validated by using receiver operating characteristic curve (ROC) and real-time PCR (RT-PCR). Our research identified hub genes related to the potential mechanism of DN and provided new lncRNA-miRNA-mRNA ceRNA network that contributed to diagnostic and potential therapeutic targets for DN.

Network pharmacology-based identification of miRNA expression of Astragalus membranaceus in the treatment of diabetic nephropathy.

ABSTRACT: Diabetic nephropathy (DN) is a common microvascular complication of diabetic patients, along with hypertension, hyperlipemia, proteinuria, edema, and other clinical manifestations. Astragalus membranaceus (AM) is a traditional Chinese medicine and has shown significant clinical efficacy against DN. However, the overall molecular mechanism of this therapeutic effect has not been entirely elucidated. Using network pharmacology, we aimed to identify the key active ingredients and potential pharmacological mechanisms of AM in treating DN and provide scientific evidence of its clinical efficacy.The active ingredients of AM were obtained from the traditional Chinese medicine systems pharmacology database, and the potential targets of AM were identified using the therapeutic target database. DN-related target genes were acquired from the Gene Expression Omnibus microarray dataset GSE1009 and 3 widely used databases-DisGeNET, GeneCards, and Comparative Toxicogenomics Database. The DN-AM common target protein interaction network was established by using the STRING database. Active ingredients candidate targets proteins networks were constructed using Cytoscape software for visualization. Additionally, gene ontology (GO) and Kyoto encyclopedia of genes and genomes pathway analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery database. Target-regulating microRNAs (miRNAs) of these hub genes were obtained from the therapeutic target database, which could then be used for further identification of AM-regulated key miRNAs.A total of 17 active ingredients and 214 target proteins were screened from AM. 61 candidate co-expressed genes with therapeutic effects against DN were obtained and considered as potential therapeutic targets. GO and Kyoto encyclopedia of genes and genomes enrichment analysis showed that these genes were mainly involved in inflammatory response, angiogenesis, oxidative stress reaction, HIF signaling pathway, tumor necrosis factor signaling pathway, and VEGF signaling pathway. In all, 636 differentially expressed genes were identified between the DN patients and control group by using microarray data, GSE1009. Lastly, VEGFA, epidermal growth factor receptor, STAT1, and GJA1 were screened as hub genes. The relationships between miRNAs and hub genes were constructed, which showed that miR-302-3p, miR-372-3p, miR-373-3p, and miR-520-3p were regulated by VEGFA and epidermal growth factor receptor. Meanwhile, VEGFA also influenced miR-15-5p, miR-16-5p, miR-17-5p, miR-20-5p, miR-93-5p, miR-106-5p, miR-195-5p, miR-424-5p, miR-497-5p, and miR-519-3p. In addition, miR-1-3p and miR-206 were regulated by VEGFA and GJA1, and miR-23-3p was regulated by STAT1 and GJA1.To our knowledge, this study revealed for the first time the characteristic multiple components, multiple targets, and multiple pathways of AM that seem to be the underlying mechanisms of action of AM in the treatment of DN with respect to miRNAs.Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval will not be required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences.

A novel electroactive plasticized polymer actuator based on chlorinated polyvinyl chloride gel.

Plasticized poly (vinyl chloride) (PVC) gel is a promising electroactive polymer material for soft actuators and sensors, and it has attracted extensive attention and interest in multi-disciplinary fields. Chlorinated polyvinyl chloride (CPVC) has enhanced mechanical and chemical properties and shows a promising potential for fabricating gel materials for electroactive polymer gel actuators. Thus, we proposed a novel soft actuator based on CPVC gels. We studied the properties of CPVC gels with various technologies, such as Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscope (SEM) analysis, thermogravimetric analysis (TGA), etc. Furthermore, CPVC gel actuators were fabricated and the influence of membrane thickness and plasticizer content on the basic characteristics was investigated. The experimental results show that the CPVC gel actuator with a higher content of DBA has a better strain than that of the actuator with lower amount of DBA despite the membrane thickness. With the same ratio of DBA, the CPVC gel actuator has a better performance than the traditional PVC gel actuator under a low applied load. The maximum strain and stress of the CPVC gel (CPVC : DBA = 1 : 2.5) actuator are 9% and 0.12 MPa respectively at 400 V, which reaches the same level of the PVC gel actuator with higher content of DBA (PVC : DBA = 1 : 4). These results demonstrate a good potential of the proposed CPVC gel soft actuator for practical application.

An Iterative Deconvolution-Time Reversal Method with Noise Reduction, a High Resolution and Sidelobe Suppression for Active Sonar in Shallow Water Environments.

Matched filtering is widely used in active sonar because of its simplicity and ease of implementation. However, the resolution performance generally depends on the transmitted waveform. Moreover, its detection performance is limited by the high-level sidelobes and seriously degraded in a shallow water environment due to time spread induced by multipath propagation. This paper proposed a method named iterative deconvolution-time reversal (ID-TR), on which the energy of the cross-ambiguity function is modeled, as a convolution of the energy of the auto-ambiguity function of the transmitted signal with the generalized target reflectivity density. Similarly, the generalized target reflectivity density is a convolution of the spread function of channel with the reflectivity density of target as well. The ambiguity caused by the transmitted signal and the spread function of channel are removed by Richardson-Lucy iterative deconvolution and the time reversal processing, respectively. Moreover, this is a special case of the Richardson-Lucy algorithm that the blur function is one-dimensional and time-invariant. Therefore, the iteration deconvolution is actually implemented by the iterative temporal time reversal processing. Due to the iterative time reversal method can focus more and more energy on the strongest target with the iterative number increasing and then the peak-signal power increases, the simulated result shows that the noise reduction can achieve 250 dB in the "ideal" free field environment and 100 dB in a strong multipaths waveguide environment if a 1-ms linear frequency modulation with a 4-kHz frequency bandwidth is transmitted and the number of iteration is 10. Moreover, the range resolution is approximately a delta function. The results of the experiment in a tank show that the noise level is suppressed by more than 70 dB and the reverberation level is suppressed by 3 dB in the case of a single target and the iteration number being 8.

Uncovering the Mechanism of Astragalus membranaceus in the Treatment of Diabetic Nephropathy Based on Network Pharmacology.

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

To Explore the Pathogenesis of Vascular Lesion of Type 2 Diabetes Mellitus Based on the PI3K/Akt Signaling Pathway.

BACKGROUND: Type 2 diabetes mellitus (T2DM) has become a chronic disease, serious harm to human health. Complications of the blood pipe are the main cause of disability and death in diabetic patients, including vascular lesions that directly affects the prognosis of patients with diabetes and survival. This study was to determine the influence of high glucose and related mechanism of vascular lesion of type 2 diabetes mellitus pathogenesis. METHODS: In vivo aorta abdominalis of GK rats was observed with blood pressure, heart rate, hematoxylin and eosin (H&E), Masson, and Verhoeff staining. In vitro cells were cultured with 30 mM glucose for 24 h. RT-QPCR was used to detect the mRNA expression of endothelial markers PTEN, PI3K, Akt, and VEGF. Immunofluorescence staining was used to detect the expression of PTEN, PI3K, Akt, and VEGF. PI3K and Akt phosphorylation levels were detected by Western blot analysis. RESULTS: Heart rate, systolic blood pressure, diastolic blood pressure, and mean blood pressure in the GK control group were higher compared with the Wistar control group and no difference compared with the GK experimental model group. Fluorescence intensity of VEGF, Akt, and PI3K in the high-sugar stimulus group was stronger than the control group; PTEN in the high-sugar stimulus group was weakening than the control group. VEGF, Akt, and PI3K mRNA in the high-sugar stimulus group were higher than the control group; protein expressions of VEGF, Akt, and PI3K in the high-sugar stimulus group were higher than the control group. PTEN mRNA in the high-sugar stimulus group was lower than the control group. Protein expression of PTEN in the high-sugar stimulus group was lower than the control group. CONCLUSIONS: Angiogenesis is an important pathogenesis of T2DM vascular disease, and PTEN plays a negative regulatory role in the development of new blood vessels and can inhibit the PI3K/Akt signaling pathway.

[Effect of Huangdi Anxiao Capsules on zebrafish vascular lesions induced by high glucose and high fat].

Zebrafish of different strains with 5 dpf (5 days post-fertilization) were selected and fed with 0.2% high-fat diet for 8 h and 3% glucose solution for 16 halternatively during the day and night for 4 consecutive days. The zebrafish model was established and randomly divided into model group, Huangdi Anxiao Capsules (260 mg·L⁻¹) group and pioglitazone (32 mg·L⁻¹) group. The drug treatment groups were given the water-soluble drugs, with a volume of 25 mL, and incubated in a 28 °C incubator for 4 days. To detect the exposure to the corresponding drugs, the normal control group was set up. Thirty zebrafish were included in each group. The effect of Huangdi Anxiao Capsules on vascular wall thickness, fluorescence intensity of islet beta cells, fluorescence intensity of macrophages, and blood flow velocity of zebrafish were detected. The expressions of vascular endothelial growth factor (vegfaa) and angiotensin converting enzyme (ACE) were detected by RT-PCR. The results showed that compared with the model group, Huangdi Anxiao Capsules can significantly reduce the thickness of the blood vessel wall, increase the fluorescence intensity of islet ß cells and macrophages, increase the blood flow velocity in vivo, and decrease the ACE and vegfaa expressions in zebrafish. It is suggested that Huangdi Anxiao Capsules may alleviate zebrafish vascular lesions by regulating the expressions of ACE and vegfaa.

Potential role of lncRNAs in contributing to pathogenesis of chronic glomerulonephritis based on microarray data.

BACKGROUND: Chronic glomerulonephritis (CGN) is the most common form of primary glomerular disease with unclear molecular mechanisms, which related to immune-mediated inflammatory diseases. Our study intended to identify potential long non-coding RNAs (lncRNAs) and genes, and to determine the potential molecular mechanisms of CGN pathogenesis. METHODS: The microarray of GSE64265 and GSE46295 were downloaded from the Gene Expression Omnibus database, GSE64265 including 3 rats control kidney tissues and 5 rats model kidney tissues, GSE46295 including 3 rats control kidney tissues and 3 rats model kidney tissues, which was on the basis of GPL1355 platform. Identification of differentially expressed lncRNAs and mRNAs were performed between the 2 groups. Gene ontology (GO) and pathway enrichment analyses were performed to analyze the biological functions and pathways for the differentially expressed mRNAs. LncRNA-mRNA weighted co-expression network was constructed using the WGCNA package to analyses for the genes in the modules. The protein-protein interaction (PPI) network was visualized. RESULTS: A total of 40 significantly up-regulated and 24 down-regulated lncRNAs, 653 up-regulated and 128 down-regulated mRNAs were identified. Additionally, Cdk1, with the highest connectivity degree in PPI network, was noteworthy enriched in cell cycle. Seven lncRNAs: NONRATT026650, LOC102547664, NONRATT77021989, NONRATT012453, LOC102551856, LOC102553536 and NONRATT7047175 were observed in the modules of lncRNA-mRNA weighted co-expression network. CONCLUSIONS: LncRNAs NONRATT026650, LOC102547664, NONRATT77021989, NONRATT012453, LOC102551856, LOC102553536 and NONRATT7047175 were differentially expressed and might play important roles in the development of CGN. Key genes, such as Cd44, Rftn1, Runx1, may be crucial biomarkers for CGN.