Deep Compressive Sensing on ECG Signals with Modified Inception Block and LSTM.

In practical electrocardiogram (ECG) monitoring, there are some challenges in reducing the data burden and energy costs. Therefore, compressed sensing (CS) which can conduct under-sampling and reconstruction at the same time is adopted in the ECG monitoring application. Recently, deep learning used in CS methods improves the reconstruction performance significantly and can removes of some of the constraints in traditional CS. In this paper, we propose a deep compressive-sensing scheme for ECG signals, based on modified-Inception block and long short-term memory (LSTM). The framework is comprised of four modules: preprocessing; compression; initial; and final reconstruction. We adaptively compressed the normalized ECG signals, sequentially using three convolutional layers, and reconstructed the signals with a modified Inception block and LSTM. We conducted our experiments on the MIT-BIH Arrhythmia Database and Non-Invasive Fetal ECG Arrhythmia Database to validate the robustness of our model, adopting Signal-to-Noise Ratio (SNR) and percentage Root-mean-square Difference (PRD) as the evaluation metrics. The PRD of our scheme was the lowest and the SNR was the highest at all of the sensing rates in our experiments on both of the databases, and when the sensing rate was higher than 0.5, the PRD was lower than 2%, showing significant improvement in reconstruction performance compared to the comparative methods. Our method also showed good recovering quality in the noisy data.

11ß­hydroxysteroid dehydrogenase­1 is associated with the activation of hepatic stellate cells in the development of hepatic fibrosis.

Hepatic fibrosis (HF) is a common complication of numerous chronic liver diseases, but predominantly results from persistent liver inflammation or injury. If left untreated, HF can progress and develop into liver cirrhosis and even hepatocellular carcinoma. However, the underlying molecular mechanisms of HF remain unknown. The present study aimed to investigate the role of 11ß­hydroxysteroid dehydrogenase­1 (11ß­HSD1) during the development of hepatic fibrosis. An experimental rat model of liver fibrosis was induced using porcine serum. 11ß­HSD1 gene expression levels and enzyme activity during hepatic fibrogenesis were assessed. 11ß­HSD1 gene knockdown using small interfering RNA and overexpression were performed in LX2­human hepatic stellate cells (HSCs). HSCs were stimulated with transforming growth factor­ß1 (TGF­ß1). Cell cycle distribution, proliferation, collagen secretion and 11ß­HSD1 gene activity in HSCs were compared before and after stimulation. As hepatic fibrosis progressed, 11ß­HSD1 gene expression and activity increased, indicating a positive correlation with typical markers of liver fibrosis. 11ß­HSD1 inhibition markedly reduced the degree of fibrosis. The cell proliferation was increased, the number of cells in the G0/G1 phase decreased and the number of cells in the S and G2/M phases increased in the pSuper transfected group compared with the N group. In addition, the overexpression of 11ß­HSD1 enhanced the TGF­ß1­induced activation of LX2­HSCs and enzyme activity of connective tissue growth factor. 11ß­HSD1 knockdown suppressed cell proliferation by blocking the G0/G1 phase of the cell cycle, which was associated with HSC stimulation and inhibition of 11ß­HSD1 enzyme activity. In conclusion, increased 11ß­HSD1 expression in the liver may be partially responsible for hepatic fibrogenesis, which is potentially associated with HSC activation and proliferation.

Role of DDAH/ADMA pathway in TGF-ß1-mediated activation of hepatic stellate cells.

Asymmetric dimethylarginine (ADMA) is catalyzed by the enzyme dimethylarginine dimethylaminohydrolase (DDAH) in humans, and the role for ADMA has been associated with hepatic fibrogenesis. Transforming growth factor­ß (TGF­ß) has been shown to mediate the myofibroblastic transformation of quiescent hepatic stellate cells (HSCs), a pivotal step in liver fibrogenesis. However, the underlying molecular mechanisms are not well understood. Accumulation of ADMA due to low activity of DDAH has been reported to be associated with liver damage and hepatic fibrosis. In this study, the role of the DDAH/ADMA pathway in the TGF­ß1­induced HSC activation was assessed. Freshly harvested primary HSCs from rat liver were used in this study. It was demonstrated that TGF­ß1 treatment significantly suppressed the DDAH protein expression and activity, and increased levels of ADMA in the culture medium of rat primary HSCs. Notably, the TGF­ß1­mediated effects on DDAH/ADMA were significantly abrogated by the p38 mitogen activated protein kinase specific inhibitor, SB203580. Furthermore, it was demonstrated that excessive ADMA led to an increase in the number of TGF­ß1­positive HSCs and induced the expression of α­smooth muscle actin and collagen type I in rat primary HSCs. In addition, rat primary HSCs exposed to excessive ADMA showed a significant increase in the expressions of α­SMA and collagen type I. Finally, it was revealed that ADMA treatment promoted the proliferation of rat primary HSCs. In conclusion, the results obtained from the study suggest a potentially novel role for the ADMA/DDAH1 signaling pathway in TGF­ß1­induced HSC activation, and along with the studies of others, suppression of the ADMA/DDAH1 pathway may be an alterative approach for the treatment of liver fibrosis.

FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity.

Bile acids are ligands for the nuclear hormone receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. We have shown that FXR and TGR5 have renoprotective roles in diabetes- and obesity-related kidney disease. Here, we determined whether these effects are mediated through differential or synergistic signaling pathways. We administered the FXR/TGR5 dual agonist INT-767 to DBA/2J mice with streptozotocin-induced diabetes, db/db mice with type 2 diabetes, and C57BL/6J mice with high-fat diet-induced obesity. We also examined the individual effects of the selective FXR agonist obeticholic acid (OCA) and the TGR5 agonist INT-777 in diabetic mice. The FXR agonist OCA and the TGR5 agonist INT-777 modulated distinct renal signaling pathways involved in the pathogenesis and treatment of diabetic nephropathy. Treatment of diabetic DBA/2J and db/db mice with the dual FXR/TGR5 agonist INT-767 improved proteinuria and prevented podocyte injury, mesangial expansion, and tubulointerstitial fibrosis. INT-767 exerted coordinated effects on multiple pathways, including stimulation of a signaling cascade involving AMP-activated protein kinase, sirtuin 1, PGC-1α, sirtuin 3, estrogen-related receptor-α, and Nrf-1; inhibition of endoplasmic reticulum stress; and inhibition of enhanced renal fatty acid and cholesterol metabolism. Additionally, in mice with diet-induced obesity, INT-767 prevented mitochondrial dysfunction and oxidative stress determined by fluorescence lifetime imaging of NADH and kidney fibrosis determined by second harmonic imaging microscopy. These results identify the renal signaling pathways regulated by FXR and TGR5, which may be promising targets for the treatment of nephropathy in diabetes and obesity.

LPS binding to HMGB1 promotes angiogenic behavior of endothelial cells through inhibition of p120 and CD31 via ERK/P38/Src signaling.

Lipopolysaccharide (LPS) is known to mediate angiogenic effects in endothelial cells. The underlying mechanisms, however, remain largely unknown. In this study, we showed that LPS induced high motility group box protein 1 (HMGB1) secretion in human pulmonary microvascular endothelial cells (HPMECs). Knockdown and overexpression of HMGB1 by adenoviral vectors effectively inhibited and promoted LPS-induced HPMEC migration and capillary-like tube formation, respectively. On the other hand, HMGB1 exerted an inhibitory effect on LPS-suppressed expression of platelet-endothelial cell adhesion molecule (CD31) and p120 catenin (p120); HMGB1 knockdown reversed this effect. These results suggest a functional synergy between LPS and HMGB1 in angiogenesis. Mechanistically, physical interaction of LPS with HMGB1 mediated dissociation of p120, ß-catenin, and γ-catenin from vascular endothelial cadherin (VE-cadherin), but without affecting VE-cadherin expression. The synergistic effect of LPS and HMGB1 was closely associated with ERK/P38/Src signaling pathway, as evidenced by the reduced degree of migration and capillary-like tube formation in HPMECs treated with signaling pathway inhibitor. Collectively, our study shows a novel mechanism whereby LPS and HMGB1 synergistically regulate the angiogenic behavior of endothelial cells.

SGLT2 Protein Expression Is Increased in Human Diabetic Nephropathy: SGLT2 PROTEIN INHIBITION DECREASES RENAL LIPID ACCUMULATION, INFLAMMATION, AND THE DEVELOPMENT OF NEPHROPATHY IN DIABETIC MICE.

There is very limited human renal sodium gradient-dependent glucose transporter protein (SGLT2) mRNA and protein expression data reported in the literature. The first aim of this study was to determine SGLT2 mRNA and protein levels in human and animal models of diabetic nephropathy. We have found that the expression of SGLT2 mRNA and protein is increased in renal biopsies from human subjects with diabetic nephropathy. This is in contrast to db-db mice that had no changes in renal SGLT2 protein expression. Furthermore, the effect of SGLT2 inhibition on renal lipid content and inflammation is not known. The second aim of this study was to determine the potential mechanisms of beneficial effects of SGLT2 inhibition in the progression of diabetic renal disease. We treated db/db mice with a selective SGLT2 inhibitor JNJ 39933673. We found that SGLT2 inhibition caused marked decreases in systolic blood pressure, kidney weight/body weight ratio, urinary albumin, and urinary thiobarbituric acid-reacting substances. SGLT2 inhibition prevented renal lipid accumulation via inhibition of carbohydrate-responsive element-binding protein-ß, pyruvate kinase L, SCD-1, and DGAT1, key transcriptional factors and enzymes that mediate fatty acid and triglyceride synthesis. SGLT2 inhibition also prevented inflammation via inhibition of CD68 macrophage accumulation and expression of p65, TLR4, MCP-1, and osteopontin. These effects were associated with reduced mesangial expansion, accumulation of the extracellular matrix proteins fibronectin and type IV collagen, and loss of podocyte markers WT1 and synaptopodin, as determined by immunofluorescence microscopy. In summary, our study showed that SGLT2 inhibition modulates renal lipid metabolism and inflammation and prevents the development of nephropathy in db/db mice.