The New Therapeutic Approaches in the Treatment of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease which is characterized by extremely complex pathogenetic mechanisms and multifactorial etiology. Some of the many pathophysiological mechanisms involved in the development of NAFLD include oxidative stress, impaired mitochondrial metabolism, inflammation, gut microbiota, and interaction between the brain-liver-axis and the regulation of hepatic lipid metabolism. The new therapeutic approaches in the treatment of NAFLD are targeting some of these milestones along the pathophysiological pathway and include drugs like agonists of peroxisome proliferator-activated receptors (PPARs), glucagon-like peptide-1 (GLP-1) agonists, sodium/glucose transport protein 2 (SGLT2) inhibitors, farnesoid X receptor (FXR) agonists, probiotics, and symbiotics. Further efforts in biomedical sciences should focus on the investigation of the relationship between the microbiome, liver metabolism, and response to inflammation, systemic consequences of metabolic syndrome.     

Alpha Ketoglutarate Exerts In Vitro Anti-Osteosarcoma Effects through Inhibition of Cell Proliferation,Induction of Apoptosis via the JNK and Caspase 9-Dependent Mechanism,and Suppression of TGF-β and VEGF Production and Metastatic Potential of Cells

Osteosarcoma (OS) is the most common type of primary bone tumor. Currently, there are limited treatment options for metastatic OS. Alpha-ketoglutarate (AKG), i.e., a multifunctional intermediate of the Krebs cycle, is one of the central metabolic regulators of tumor fate and plays an important role in cancerogenesis and tumor progression. There is growing evidence suggesting that AKG may represent a novel adjuvant therapeutic opportunity in anti-cancer therapy. The present study was intended to check whether supplementation of Saos-2 and HOS osteosarcoma cell lines (harboring a TP53 mutation) with exogenous AKG exerted an anti-cancer effect. The results revealed that AKG inhibited the proliferation of both OS cell lines in a concentration-dependent manner. As evidenced by flow cytometry, AKG blocked cell cycle progression at the G₁ stage in both cell lines, which was accompanied by a decreased level of cyclin D1 in HOS and increased expression of p21^Waf1/Cip1 protein in Saos-2 cells (evaluated with the ELISA method). Moreover, AKG induced apoptotic cell death and caspase-3 activation in both OS cell lines (determined by cytometric analysis). Both the immunoblotting and cytometric analysis revealed that the AKG-induced apoptosis proceeded predominantly through activation of an intrinsic caspase 9-dependent apoptotic pathway and an increased Bax/Bcl-2 ratio. The apoptotic process in the AKG-treated cells was mediated via c-Jun N-terminal protein kinase (JNK) activation, as the specific inhibitor of this kinase partially rescued the cells from apoptotic death. In addition, the AKG treatment led to reduced activation of extracellular signal-regulated kinase (ERK1/2) and significant inhibition of cell migration and invasion in vitro concomitantly with decreased production of pro-metastatic transforming growth factor β (TGF-β) and pro-angiogenic vascular endothelial growth factor (VEGF) in both OS cell lines suggesting the anti-metastatic potential of this compound. In conclusion, we showed the anti-osteosarcoma potential of AKG and provided a rationale for a further study of the possible application of AKG in OS therapy.     

Structural and Functional Differences between Homologous Bacterial Ribonucleases

Small cationic guanyl-preferring ribonucleases (RNases) produced by the Bacillus species share a similar protein tertiary structure with a high degree of amino acid sequence conservation. However, they form dimers that differ in conformation and stability. Here, we have addressed the issues (1) whether the homologous RNases also have distinctions in catalytic activity towards different RNA substrates and interactions with the inhibitor protein barstar, and (2) whether these differences correlate with structural features of the proteins. Circular dichroism and dynamic light scattering assays revealed distinctions in the structures of homologous RNases. The activity levels of the RNases towards natural RNA substrates, as measured spectrometrically by acid-soluble hydrolysis products, were similar and decreased in the row high-polymeric RNA >>> transport RNA > double-stranded RNA. However, stopped flow kinetic studies on model RNA substrates containing the guanosine residue in a hairpin stem or a loop showed that the cleavage rates of these enzymes were different. Moreover, homologous RNases were inhibited by the barstar with diverse efficiency. Therefore, minor changes in structure elements of homologous proteins have a potential to significantly effect molecule stability and functional activities, such as catalysis or ligand binding.     

超宽带多注速调管的模拟研究

本文介绍了多注速调管的发展历史和现状,以及速调管模拟软件的发展情况。用1．5维软件KIystron-MSU和2．5维软件Arsenal-MSU对超宽带多注速调管进行了设计计算,并对计算结果进行分析,得到了比较好的输出特性。计算结果表明可以实现该超宽带多注速调管,其带宽10-14％,增益40～50dB,效率40～50％。     

Human Recombinant DNase I (Pulmozyme®) Inhibits Lung Metastases in Murine Metastatic B16 Melanoma Model That Correlates with Restoration of the DNase Activity and the Decrease SINE/LINE and c-Myc Fragments in Blood Cell-Free DNA

Tumor-associated cell-free DNAs (cfDNA) play an important role in the promotion of metastases. Previous studies proved the high antimetastatic potential of bovine pancreatic DNase I and identified short interspersed nuclear elements (SINEs) and long interspersed nuclear elements (LINEs)and fragments of oncogenes in cfDNA as the main molecular targets of enzyme in the bloodstream. Here, recombinant human DNase I (commercial name Pulmozyme^®), which is used for the treatment of cystic fibrosis in humans, was repurposed for the inhibition of lung metastases in the B16 melanoma model in mice. We found that Pulmozyme^® strongly reduced migration and induced apoptosis of B16 cells in vitro and effectively inhibited metastases in lungs and liver in vivo. Pulmozyme^® was shown to be two times more effective when administered intranasally (i.n.) than bovine DNase I, but intramuscular (i.m.) administration forced it to exhibit as high an antimetastatic activity as bovine DNase I. Both DNases administered to mice either i.m. or i.n. enhanced the DNase activity of blood serum to the level of healthy animals, significantly decreased cfDNA concentrations, efficiently degraded SINE and LINE repeats and c-Myc fragments in the bloodstream and induced apoptosis and disintegration of neutrophil extracellular traps in metastatic foci; as a result, this manifested as the inhibition of metastases spread. Thus, Pulmozyme^®, which is already an approved drug, can be recommended for use in the treatment of lung metastases.     

The perspectives of natural deep eutectic solvents in agri-food sector

Abstract

The principles of ‘green chemistry’ are gaining importance in agri-food sector due to the need to reduce pollution from toxic chemicals, make industrial processes safer and more sustainable, and to offer ‘clean-labeled products’ required by the consumers. The application of natural deep eutectic solvents (NADES) – natural product-based green liquids is considered the promising alternative to conventional organic solvents. This review is intended to summarize and discuss recent advances related to physicochemical properties of NADES, their applications, compatibility with analytic techniques and toxicological profile, pointing out the challenges and necessary improvements for their wider utilization in agri-food sector. NADES allow extraction of wide range of food compounds and they are proven to be convenient for food-related applications. However, their potential for industrial scale-up utilization is not completely investigated. Examined NADES are readily biodegradable, but only preliminary studies on NADES toxicity which include limited number of NADES molecules are available. Apart from fundamental research dealing with NADES formation and the nature of the interactions and structure underpinning the liquid phase formation, the question of purity of NADES obtained by different synthetic methodologies need to be addressed in the future. Data on physicochemical properties of synthetized NADES are still needed as they are relevant for industrial applications.     

Effect of noisy carrier reference signal and interference on performance of MSK receiver

This paper considers the coherent detection of minimum shift keying signal and a degradation in error rate performance from ideal due to an interference and a phase discrepancy between the carrier of the received signal and the carrier of the receiver. The error rate is calculated for the simple receiver model with integrate‐and‐dump circuits. The reference carrier signal unsteadiness is presented by the probability density function of the first order non‐linear PLL phase error, while the uncertainty due to an interference is involved in the system model with a random phase of cosine signal that accompanied the useful signal. Copyright © 2004 John Wiley & Sons, Ltd.