2-Deoxyglucose, an Inhibitor of Glycolysis, Enhances the Oncolytic Effect of Coxsackievirus.

Glioblastoma multiforme (GBM) is one of the most common types of brain tumor. Despite intensive research, patients with GBM have a poor prognosis due to a very high rate of relapse and significant side effects of the treatment, with a median survival of 14.6 months. Oncolytic viruses are considered a promising strategy to eliminate GBM and other types of cancer, and several viruses have already been introduced into clinical practice. However, identification of the factors that underly the sensitivity of tumor species to oncolytic viruses or that modulate their clinical efficacy remains an important target. Here, we show that Coxsackievirus B5 (CVB5) demonstrates high oncolytic potential towards GBM primary cell species and cell lines. Moreover, 2-deoxyglucose (2DG), an inhibitor of glycolysis, potentiates the cytopathic effects of CVB5 in most of the cancer cell lines tested. The cells in which the inhibition of glycolysis enhanced oncolysis are characterized by high mitochondrial respiratory activity and glycolytic capacity, as determined by Seahorse analysis. Thus, 2-deoxyglucose and other analogs should be considered as adjuvants for oncolytic therapy of glioblastoma multiforme.

Multiomic Profiling Identified EGF Receptor Signaling as a Potential Inhibitor of Type I Interferon Response in Models of Oncolytic Therapy by Vesicular Stomatitis Virus.

Cancer cell lines responded differentially to type I interferon treatment in models of oncolytic therapy using vesicular stomatitis virus (VSV). Two opposite cases were considered in this study, glioblastoma DBTRG-05MG and osteosarcoma HOS cell lines exhibiting resistance and sensitivity to VSV after the treatment, respectively. Type I interferon responses were compared for these cell lines by integrative analysis of the transcriptome, proteome, and RNA editome to identify molecular factors determining differential effects observed. Adenosine-to-inosine RNA editing was equally induced in both cell lines. However, transcriptome analysis showed that the number of differentially expressed genes was much higher in DBTRG-05MG with a specific enrichment in inflammatory proteins. Further, it was found that two genes, EGFR and HER2, were overexpressed in HOS cells compared with DBTRG-05MG, supporting recent reports that EGF receptor signaling attenuates interferon responses via HER2 co-receptor activity. Accordingly, combined treatment of cells with EGF receptor inhibitors such as gefitinib and type I interferon increases the resistance of sensitive cell lines to VSV. Moreover, sensitive cell lines had increased levels of HER2 protein compared with non-sensitive DBTRG-05MG. Presumably, the level of this protein expression in tumor cells might be a predictive biomarker of their resistance to oncolytic viral therapy.

Role of silymarin as antioxidant in clinical management of chronic liver diseases: a narrative review.

Chronic liver disease (CLD), manifested as hepatic injury, is a major cause of global morbidity and mortality. CLD progresses to fibrosis, cirrhosis, and-ultimately-hepatocellular carcinoma (HCC) if left untreated. The different phenotypes of CLD based on their respective clinical features and causative agents include alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), metabolic-associated fatty liver disease (MAFLD), and drug-induced liver injury (DILI). The preferred treatment modality for CLD includes lifestyle modification and diet, along with limited pharmacological agents for symptomatic treatment. Moreover, oxidative stress (OS) is an important pathological mechanism underlying all CLD phenotypes; hence, the use of antioxidants to manage the disease is justified. Based on available clinical evidence, silymarin can be utilized as a hepatoprotective agent, given its potent antioxidant, antifibrotic, and anti-inflammatory properties. The role of silymarin in suppressing OS has been well established, and therefore silymarin is recommended for use in ALD and NAFLD in the guidelines approved by the Russian Medical Scientific Society of Therapists and the Gastroenterology Scientific Society of Russia. However, to discuss the positioning of the original silymarin in clinical guidelines and treatment protocols as a hepatoprotective agent for managing CLD concomitantly with other therapies, an expert panel of international and Russian medical professionals was convened on 11 November 2020. The panel reviewed approaches for the prevention and treatment of OS, existing guidelines for patient management for CLD, and available evidence on the effectiveness of silymarin in reducing OS, fibrosis, and hepatic inflammation and presented in the form of a narrative review. Key messagesAn expert panel of international and Russian medical professionals reviewed existing guidelines for ALD, NAFLD, MAFLD, and DILI to establish consensus recommendations that oxidative stress is the common pathophysiological mechanism underlying these conditions.The panel also discussed the positioning of original silymarin in clinical guidelines and treatment protocols as a hepatoprotective agent for managing CLD concomitantly with other therapies.The panel reviewed the effectiveness of 140 mg original silymarin three times a day in reducing oxidative stress in chronic liver diseases such as ALD, NAFLD, MAFLD, and DILI.

Short-Term Reloading After Prolonged Unloading Ensures Restoration of Stromal but Not Hematopoietic Precursor Activity in Tibia Bone Marrow of C57Bl/6N Mice.

Bone and muscle tissues are mostly susceptible to different kinds of hypodynamia, including real and simulated microgravity (sµg). To evaluate the effect of sµg on bone marrow (BM), male C57Bl/6N mice were divided into three groups: vivarium control (VC), 30-day hindlimb suspension (HS), and subsequent 12-h short-term support reloading (RL). The effects on BM total mononucleated cells (MNCs) as well as stromal and hematopoietic progenitors from murine tibia were studied. The number of BM MNCs, immunophenotype, proliferation, colony-forming units (CFUs), differentiation and secretory activity of hematopoietic and stromal BM cells were determined. HS led to a twofold decrease in MNCs, alteration of surface molecule expression profiles, suppression of proliferative activity of BM cells, and change of soluble mediators' levels. The stromal compartment was characterized by a decrease of CFU of fibroblasts and suppression of spontaneous osteo-commitment after HS. Among the hematopoietic precursors, a decrease in the total number of CFUs was found mainly at the expense of suppression of CFU-GM and CFU-GEMM. After RL, restoration of the stromal precursor's functional activity to control levels and overabundance of paracrine mediator's production were detected, whereas the complete recovery of hematopoietic precursor's activity did not occur. These data demonstrate the fast functional reaction of the stromal compartment on restoration of loading support.

Effects of Siberian fir terpenes extract Abisil on antioxidant activity, autophagy, transcriptome and proteome of human fibroblasts.

BACKGROUND: Abisil is an extract of Siberian fir terpenes with antimicrobial and wound healing activities. Previous studies revealed that Abisil has geroprotective, anti-tumorigenic, and anti-angiogenic effects. Abisil decreased the expression of cyclin D1, E1, A2, and increased the phosphorylation rate of AMPK. OBJECTIVE: In the present study, we analyzed the effect of Abisil on autophagy, the mitochondrial potential of embryonic human lung fibroblasts. We evaluated its antioxidant activity and analyzed the transcriptomic and proteomic effects of Abisil treatment. RESULTS: Abisil treatment resulted in activation of autophagy, reversal of rotenone-induced elevation of reactive oxygen species (ROS) levels and several-fold decrease of mitochondrial potential. Lower doses of Abisil (25 µg/ml) showed a better oxidative effect than high doses (50 or 125 µg/ml). Estimation of metabolic changes after treatment with 50 µg/ml has not shown any changes in oxygen consumption rate, but extracellular acidification rate decreased significantly. Abisil treatment (5 and 50 µg/ml) of MRC5-SV40 cells induced a strong transcriptomic shift spanning several thousand genes (predominantly, expression decrease). Among down-regulated genes, we noticed an over-representation of genes involved in cell cycle progression, oxidative phosphorylation, and fatty acid biosynthesis. Additionally, we observed predominant downregulation of genes encoding for kinases. Proteome profiling also revealed that the content of hundreds of proteins is altered after Abisil treatment (mainly, decreased). These proteins were involved in cell cycle regulation, intracellular transport, RNA processing, translation, mitochondrial organization. CONCLUSIONS: Abisil demonstrated antioxidant and autophagy stimulating activity. Treatment with Abisil results in the predominant downregulation of genes involved in the cell cycle and oxidative phosphorylation.

Crystal structure, phase transition and structural deformations in iron borate (Y0.95Bi0.05)Fe3(BO3)4 in the temperature range 90-500†K.

An accurate X-ray diffraction study of (Y0.95Bi0.05)Fe3(BO3)4 single crystals in the temperature range 90-500 K was performed on a laboratory diffractometer and used synchrotron radiation. It was established that the crystal undergoes a diffuse structural phase transition in the temperature range 350-380 K. The complexity of localization of such a transition over temperature was overcome by means of special analysis of systematic extinction reflections by symmetry. The transition temperature can be considered to be Tstr ≃ 370 K. The crystal has a trigonal structure in the space group P3121 at temperatures of 90-370 K, and it has a trigonal structure in the space group R32 at 375-500 K. There is one type of chain formed by the FeO6 octahedra along the c axis in the R32 phase. When going into the P3121 phase, two types of nonequivalent chains arise, in which Fe atoms are separated from the Y atoms by a different distance. Upon lowering the temperature from 500 to 90 K, a distortion of the Y(Bi)O6, FeO6, B(2,3)O3 coordination polyhedra is observed. The distances between atoms in helical Fe chains and Fe-O-Fe angles change non-uniformly. A sharp jump in the equivalent isotropic displacement parameters of O1 and O2 atoms within the Fe-Fe chains and fluctuations of the equivalent isotropic displacement parameters of B2 and B3 atoms were observed in the region of structural transition as well as noticeable elongation of O1, O2, B2, B3, Fe1, Fe2 atomic displacement ellipsoids. It was established that the helices of electron density formed by Fe, O1 and O2 atoms may be structural elements determining chirality, optical activity and multiferroicity of rare-earth iron borates. Compression and stretching of these helices account for the symmetry change and for the manifestation of a number of properties, whose geometry is controlled by an indirect exchange interaction between iron cations that compete with the thermal motion of atoms in the structure. Structural analysis detected these changes as variations of a number of structural characteristics in the c unit-cell direction, that is, the direction of the helices. Structural results for the local surrounding of the atoms in (Y0.95Bi0.05)Fe3(BO3)4 were confirmed by EXAFS and Mössbauer spectroscopies.