Prediction model for cognitive impairment in maintenance hemodialysis patients.

PURPOSE: To explore the risk factors for cognitive impairment in patients undergoing maintenance hemodialysis (MHD) and construct a predictive model for cognitive impairment. METHODS: A total of 146 patients with end-stage renal disease (ESRD) undergoing MHD were recruited at our hospital between December 2021 and April 2022. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), and scores of < 26 were considered indicative of cognitive impairment. Risk factors were identified using a multivariate logistic regression model, and a receiver operating characteristic curve was applied to construct the prediction model. Cognitive impairment risk was categorized using a multifactorial prediction model based on the weight of evidence. RESULTS: 46 patients with cognitive impairment were identified, with a prevalence of 31.5% in ESRD patients undergoing MHD. Multivariate logistic regression analyses indicated that the following factors were associated with an increased risk of cognitive impairment in patients undergoing MHD: aged 55.0-64.0 years (OR:6.24; 95%CI:1.81-21.48; P = 0.001), aged 65.0-74.0 years (OR:16.10; 95%CI:4.03-64.37; P < 0.001), aged ≥ 75.0 years (OR:90.22; 95%CI:16.86-482.86; P < 0.001), duration of dialysis ≥ 5 years (OR:3.99; 95%CI:1.58-10.04; P = 0.003), and current smoker (OR:4.61; 95%CI:1.46-14.57; P = 0.009). The predictive value of the constructed model based on the aforementioned factors for cognitive impairment was 84% (95%CI,77-91%). The prevalence of cognitive impairment for patients at low, moderately low, moderately high, and high risk was 0% (95%CI:0-17%), 10% (95%CI:3-22%), 32% (95%CI:16-52%), and 65% (95%CI:50-78%), respectively. CONCLUSIONS: This study constructed a multifactorial prediction model with a high predictive value for cognitive impairment in patients with ESRD undergoing MHD.

Lycium barbarum polysaccharide-glycoprotein promotes osteogenesis in hPDLSCs via ERK activation.

OBJECTIVE: A lack of relevant research on Lycium barbarum polysaccharide-glycoprotein (LBP) application in oral diseases. Here, we focused on the effect of LBP on osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and periodontitis bone loss. METHODS: Human periodontal ligament stem cells (hPDLSCs) were isolated and identified by flow cytometry. Alkaline phosphatase (ALP) activity, Alizarin Red staining, and combined qPCR and Western blot analyses were performed to elucidate the effects of LBP on the osteogenic potential of hPDLSCs. In vivo experiments were performed with the treatment of LBP in rat periodontal model. MicroCT scanning and histological analysis were conducted to evaluate osteogenesis in situ. RESULTS: Human periodontal ligament stem cells (hPDLSCs) were successfully isolated and identified with CD90, CD29, and CD45. LBP enhanced hPDLSCs proliferation and migration and promoted RUNX2, ALP, Collagen I, and Osteocalcin expression through activating the ERK1/2 signaling pathway in vitro. The inflammatory factors, including interleukin 6 (IL-6) and interleukin 8 (IL-8) were reduced after LBP treatment. Alveolar bone resorption was significantly decreased in the LBP-treated groups in vivo, and osteoclast was markedly decreased by LBP application. CONCLUSION: LBP promoted hPDLSC osteogenesis by targeting the ERK1/2 signaling pathway and reverse bone loss by reducing inflammation. These findings provided latent hope for LBP application in periodontal therapy.

Bone marrow mesenchymal stem cell-derived exosomes loaded with miR-26a through the novel immunomodulatory peptide DP7-C can promote osteogenesis.

PURPOSE: As small bioactive molecules, exosomes can deliver osteogenesis-related miRNAs to target cells and promote osteogenesis. This study aimed to investigate miR-26a as a therapeutic cargo to be loaded into bone marrow stromal cell exosomes through a novel immunomodulatory peptide (DP7-C). METHODS: After transfecting BMSCs with DP7-C as a transfection agent, exosomes were extracted by ultracentrifugation from the culture supernatant of miR-26a-modified BMSCs. We then characterized and identified the engineered exosomes. The effect of the engineered exosomes on osteogenesis was then evaluated in vitro and in vivo, including transwell, wound healing, modified alizarin red staining, western blot, real-time quantitative PCR, and experimental periodontitis assays. Bioinformatics and data analyses were conducted to investigate the role of miR-26a in bone regeneration. RESULTS: The DP7-C/miR-26a complex successfully transfected miR-26a into BMSCs and stimulated them to release more than 300 times the amount of exosomes overexpressing miR-26a compared with the ExoNC group. Furthermore, exosomes loaded with miR-26a could enhance proliferation, migration, and osteogenic differentiation of BMSCs in vitro compared with the ExoNC and blank groups. In vivo, the ExomiR-26a group inhibited the destruction of periodontitis compared with the ExoNC and blank groups, as revealed by HE staining. Micro-CT indicated that treatment of ExomiR-26a increased the percent bone volume and the bone mineral density compared with those of the ExoNC (P < 0.05) and blank groups (P < 0.001). Target gene analysis indicated that the osteogenic effect of miR-26a is related to the mTOR pathway. CONCLUSION: miR-26a can be encapsulated into exosomes through DP7-C. Exosomes loaded with miR-26a can promote osteogenesis and inhibit bone loss in experimental periodontitis and serve as the foundation for a novel treatment strategy.

A grooved porous hydroxyapatite scaffold induces osteogenic differentiation via regulation of PKA activity by upregulating miR-129-5p expression.

BACKGROUND AND OBJECTIVE: Hydroxyapatite scaffolds with different morphologies have been widely used in bone tissue engineering. Moreover, microRNAs (miRNAs) have been proven to be extensively involved in regulating bone regeneration. We developed grooved porous hydroxyapatite (HAG) scaffolds with good osteogenic efficiency. However, little is known about the role of miRNAs in HAG scaffold-mediated promotion of bone regeneration. The objective of this study was to reveal the mechanism from the perspective of differential miRNA expression. METHODS: Scanning electron microscopy (SEM) was used to perform the coculture of cells and scaffolds. The miRNA profiles were generated by a microarray assay. A synthetic miR-129-5p mimic and inhibitor were used for overexpression or inhibition. The expression of osteogenic marker mRNAs and proteins was detected by quantitative real-time PCR (qRT-PCR), Western blotting, and immunofluorescence. An ALP activity kit and alizarin red staining (ARS) were used to measure ALP activity and mineral deposition formation. Cell migration ability was examined by wound healing and transwell assays. Protein kinase A (PKA) activity was measured by enzyme-linked immunosorbent assay (ELISA) after miR-129-5p transfection. Target genes were identified by a dual-luciferase reporter assay. H89 preculture evaluated the cross talk between miR-129-5p and PKA activity. Heterotopic implantation models, hematoxylin-eosin (HE), immunohistochemistry staining, and micro-CT were used to evaluate miR-129-5p osteogenesis in vivo. RESULTS: miRNAs were differentially expressed during osteogenic differentiation induced by HAG in vitro and in vivo. miR-129-5p was the only highly expressed miRNA both in vitro and in vivo. miR-129-5p overexpression promoted osteoblast differentiation and cell migration, while its inhibition weakened the effect of HAG. Moreover, miR-129-5p activated PKA to regulate the phosphorylation of ß-catenin and cAMP-response element binding protein (CREB) by inhibiting cAMP-dependent protein kinase inhibitor alpha (Pkia). H89 prevented the effects of miR-129-5p on osteogenic differentiation and cell migration. HE, immunohistochemistry staining and micro-CT results showed that miR-129-5p promoted in vivo osteogenesis of the HAG scaffold. CONCLUSION: The HAG scaffold activates Pka by upregulating miR-129-5p and inhibiting Pkia, resulting in CREB-dependent transcriptional activation and accumulation of ß-catenin and promoting osteogenic marker expression.

Emulsion template fabricated heterogeneous bilayer gelatin-based scaffolds with sustained-delivery of lycium barbarum glycopeptide for periodontitis treatment.

Periodontitis is a chronic inflammatory disease raising the risks of tooth-supporting structures destruction and even tooth loss. The way to reconstruct periodontal bone tissues in inflammatory microenvironment has been long in demand for periodontitis treatment. In this study, the lycium barbarum glycopeptide (LbGP) loaded gelatin-based scaffolds were fabricated for periodontitis treatment. Gelatin microspheres with suitable size were prepared by emulsification and gathered by oxidized sodium alginate to prepare heterogeneous bilayer gelatin-based scaffolds, and then they were loaded with LbGP. The prepared scaffolds possessed interconnected porous microstructures, good degradation properties, sufficient mechanical properties, sustained release behavior and well biocompatibility. In vitro experiments suggested that the LbGP loaded gelatin-based scaffolds could inhibit the expression of inflammatory factors (IL-1ß, IL-6, and TNF-α), promote the expression of anti-inflammatory factor (IL-10), and the expression of osteogenic markers (BMP2, Runx2, ALP, and OCN) in PDLSCs under the LPS-stimulated inflammatory microenvironment. Moreover, in rat periodontitis models, the LbGP gelatin-based scaffolds would reduce the alveolar bone resorption of rats, increase the collagen fiber content of periodontal membrane, alleviate local inflammation and improve the expression of osteogenesis-related factors. Therefore, the LbGP loaded gelatin-based scaffolds in this study will provide a potential therapeutic strategy for periodontitis treatment.

miR-210-3p suppresses osteogenic differentiation of MC3T3-E1 by targeting brain derived neurotrophic factor (BDNF).

BACKGROUND AND OBJECTIVE: As an important mediator of intercellular interaction and formation of extracellular bone matrix, porous scaffolds are widely used for bone regeneration. Accumulating evidences demonstrate that microRNA are involved in the regulation of scaffolds-induced bone regeneration. Recently, we revealed that miR-210-3p was highly expressed during osteogenesis induced by HAG. In present study, we further explored the molecular mechanism underlying the effect of miR-210-3p on osteogenic differentiation. MATERIALS AND METHODS: In this study, miR-210-3p mimics and inhibitors were synthesized and transfected into MC3T3-E1 cells to explore their effects on osteogenic differentiation. The expression of osteogenic marker (Alp and Runx2) were detected by real-time quantitative PCR (qRT-PCR) and western blotting. After osteogenesis induction for 7 days, Alp staining were used to detected osteoblast differentiation of MC3T3-E1 cells. CCK8 and Transwell assays were performed to detected cell proliferation and migration. Then, top ranking list of target genes of miR-210-3p obtained from TargetScan and the expression of BDNF were detected by qRT-PCR and ELISA. The relationship between miR-210-3p and BDNF was verified by luciferase report assay. Furthermore, the effect of BDNF on osteoblast differentiation was verified by transfecting siRNA or adding BDNF to the culture medium. RESULTS: MiR-210-3p mimics markedly suppress osteogenic differentiation, cell migration and cell proliferation of MC3T3-E; nevertheless, silencing of miR-210-3p dramatically enhanced MC3T3-E1 osteogenesis, cell migration and proliferation. Furthermore, luciferase reporter assay verified that brain derived neurotrophic factor (BDNF) is a directly target of miR-210-3p. Moreover, BDNF siRNA significantly decreased the expression levels of ALP and cell migration. The addition of BDNF partially rescued the inhibition of osteogenesis by miR-210-3p. CONCLUSION: miR-210-3p inhibited the osteogenic differentiation via targeting BDNF. Our Results provide a promising target for regulating osteogenic differentiation.

Identification of Key Candidate Genes and Chemical Perturbagens in Diabetic Kidney Disease Using Integrated Bioinformatics Analysis.

Globally, nearly 40 percent of all diabetic patients develop serious diabetic kidney disease (DKD). The identification of the potential early-stage biomarkers and elucidation of their underlying molecular mechanisms in DKD are required. In this study, we performed integrated bioinformatics analysis on the expression profiles GSE111154, GSE30528 and GSE30529 associated with early diabetic nephropathy (EDN), glomerular DKD (GDKD) and tubular DKD (TDKD), respectively. A total of 1,241, 318 and 280 differentially expressed genes (DEGs) were identified for GSE30258, GSE30529, and GSE111154 respectively. Subsequently, 280 upregulated and 27 downregulated DEGs shared between the three GSE datasets were identified. Further analysis of the gene expression levels conducted on the hub genes revealed SPARC (Secreted Protein Acidic And Cysteine Rich), POSTN (periostin), LUM (Lumican), KNG1 (Kininogen 1), FN1 (Fibronectin 1), VCAN (Versican) and PTPRO (Protein Tyrosine Phosphatase Receptor Type O) having potential roles in DKD progression. FN1, LUM and VCAN were identified as upregulated genes for GDKD whereas the downregulation of PTPRO was associated with all three diseases. Both POSTN and SPARC were identified as the overexpressed putative biomarkers whereas KNG1 was found as downregulated in TDKD. Additionally, we also identified two drugs, namely pidorubicine, a topoisomerase inhibitor (LINCS ID- BRD-K04548931) and Polo-like kinase inhibitor (LINCS ID- BRD-K41652870) having the validated role in reversing the differential gene expression patterns observed in the three GSE datasets used. Collectively, this study aids in the understanding of the molecular drivers, critical genes and pathways that underlie DKD initiation and progression.

Retention-Aware DRAM Auto-Refresh Scheme for Energy and Performance Efficiency.

Dynamic random access memory (DRAM) circuits require periodic refresh operations to prevent data loss. As DRAM density increases, DRAM refresh overhead is even worse due to the increase of the refresh cycle time. However, because of few the cells in memory that have lower retention time, DRAM has to raise the refresh frequency to keep the data integrity, and hence produce unnecessary refreshes for the other normal cells, which results in a large refresh energy and performance delay of memory access. In this paper, we propose an integration scheme for DRAM refresh based on the retention-aware auto-refresh (RAAR) method and 2x granularity auto-refresh simultaneously. We also explain the corresponding modification need on memory controllers to support the proposed integration refresh scheme. With the given profile of weak cells distribution in memory banks, our integration scheme can choose the most appropriate refresh technique in each refresh time. Experimental results on different refresh cycle times show that the retention-aware refresh scheme can properly improve the system performance and have a great reduction in refresh energy. Especially when the number of weak cells increased due to the thermal effect of 3D-stacked architecture, our methodology still keeps the same performance and energy efficiency.

Low calcium dialysate combined with CaCO3 in hyperphosphatemia in hemodialysis patients.

This aim of this study was to observe the effects of the application of low calcium dialysate (LCD) combined with oral administration of CaCO3 in the treatment of hyperphosphatemia, as well as blood Ca2+, calcium-phosphate product (CPP), parathyroid hormone (PTH) and blood pressure in patients undergoing hemodialysis. Thirty-one maintenance hemodialysis (MHD) patients with hyperphosphatemia, but normal blood Ca2+, underwent dialysis with an initial dialy-sate Ca2+ concentration (DCa) of 1.50 mmol/l for six months and then with 1.25 mmol/l for six months. The patients who underwent dialysis with a DCa of 1.25 mmol/l were treated orally with 0.3 g CaCO3 tablets three times a day. In the third and sixth months [observation end point (OEP)] of the dialysis, the concentrations of Ca2+, phosphorus and intact PTH (iPTH) were measured; blood pressure and side-effects prior to and following dialysis were also observed. The Ca2+, CPP and iPTH levels increased (P<0.05) in the sixth month of treatment with a DCa of 1.50 mmol/l. However, the Ca2+ concentration declined to a certain degree, CPPs decreased significantly (P<0.05) and the iPTH concentration increased following treatment with a DCa of 1.25 mmol/l for six months. The incidence rate of adverse effects of LCD was 12.9% (4/31); the effects were mainly muscle spasms, hypotension and elevated PTH. The periodic application of LCD combined with the oral administration of CaCO3 effectively reduced serum phosphorus and CPPs among MHD patients with hyperphosphatemia, indicating that the treatment may be used clinically.