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Michal Selc,1,2 Radka Macova,2,3 Andrea Babelova1,2 1Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, Slovakia; 2Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia; 3Department of Genetics, Faculty of Natural Sciences, Comenius University Bratislava, Bratislava, SlovakiaCorrespondence: Michal Selc, Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, 84511, Slovakia, Tel +421-2-32295-175, Email michal.selc@savba.skAbstract: Silibinin, a bioactive component found in milk thistle extract (Silybum marianum), is known to have significant therapeutic potential in the treatment of various liver diseases. It is considered a key element of silymarin, which is traditionally used to support liver function. The main mechanisms of action of silibinin are attributed to its antioxidant properties protecting liver cells from damage caused by free radicals. Experimental studies conducted in vitro and in vivo have confirmed its ability to inhibit inflammatory and fibrotic processes, as well as promote the regeneration of damaged liver tissue. Therefore, silibinin represents a promising tool for the treatment of liver diseases. Since the silibinin molecule is insoluble in water and has poor bioavailability in vivo, new perspectives on solving this problem are being sought. The two most promising approaches are the water-soluble derivative silibinin-C-2’,3-dihydrogen succinate, disodium salt, and the silibinin-phosphatidylcholine complex. Both drugs are currently under evaluation in liver disease clinical trials. Nevertheless, the mechanism underlying silibinin biological activity is still elusive and its more detailed understanding would undoubtedly increase its potential in the development of effective therapeutic strategies against liver diseases. This review is focused on the therapeutic potential of silibinin and its derivates, approaches to increase the bioavailability and the benefits in the treatment of liver diseases that have been achieved so far. The review discusses the relevant in vitro and in vivo studies that investigated the protective effects of silibinin in various forms of liver damage. Keywords: silybin, bioavailability, liver disease, silibinin-phosphatidylcholine complex, silibinin-C-2‘ 3-dihydrogen succinate

Kristina Jakic,1 Michal Selc,1,2 Filip Razga,3 Veronika Nemethova,3 Petra Mazancova,3 Filip Havel,4,5 Michal Sramek,5 Monika Zarska,5 Jan Proska,4 Vlasta Masanova,6 Iveta Uhnakova,6 Peter Makovicky,7 Marta Novotova,8 Vit Vykoukal,9 Andrea Babelova1,2 1Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia; 2Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, Slovakia; 3Selecta Biotech SE, Bratislava, Slovakia; 4Department of Physical Electronics, Faculty of Nuclear Sciences and Physical Engineering, Czech Technical University in Prague, Prague, Czech Republic; 5Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic; 6Department of Metallomics, Faculty of Medicine, Slovak Medical University, Bratislava, Slovakia; 7Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia; 8Department of Cellular Cardiology, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia; 9Department of Chemistry, Faculty of Science, Masaryk University, Brno, Czech RepublicCorrespondence: Andrea Babelova, Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia, Tel +421-2-32295-189, Fax +421-2-5477-4284, Email andrea.babelova@savba.skIntroduction: Gold nanoparticles are promising candidates as vehicles for drug delivery systems and could be developed into effective anticancer treatments. However, concerns about their safety need to be identified, addressed, and satisfactorily answered. Although gold nanoparticles are considered biocompatible and nontoxic, most of the toxicology evidence originates from in vitro studies, which may not reflect the responses in complex living organisms.Methods: We used an animal model to study the long-term effects of 20 nm spherical AuNPs coated with bovine serum albumin. Mice received a 1 mg/kg single intravenous dose of nanoparticles, and the biodistribution and accumulation, as well as the organ changes caused by the nanoparticles, were characterized in the liver, spleen, and kidneys during 120 days.Results: The amount of nanoparticles in the organs remained high at 120 days compared with day 1, showing a 39% reduction in the liver, a 53% increase in the spleen, and a 150% increase in the kidneys. The biological effects of chronic nanoparticle exposure were associated with early inflammatory and fibrotic responses in the organs and were more pronounced in the kidneys, despite a negligible amount of nanoparticles found in renal tissues.Conclusion: Our data suggest, that although AuNPs belong to the safest nanomaterial platforms nowadays, due to their slow tissue elimination leading to long-term accumulation in the biological systems, they may induce toxic responses in the vital organs, and so understanding of their long-term biological impact is important to consider their potential therapeutic applications. Keywords: AuNPs, in vivo, long-term accumulation, biodistribution, inflammation, fibrosis

The prevalence of arterial hypertension (AH) affecting the adult population in Europe is around 30 to 40 %. The primary goal in the treatment of AH is the permanent reduction of the overall risk of cardiovascular morbidity and mortality. Initial monotherapy is recommended for very-high-risk patients with a high-normal blood pressure, as well as, (for cautionary reasons) for very old and frail patients. It may also be considered in low-risk patients with stage 1 hypertension whose systolic blood pressure (BP) is more modestly elevated. In most patients, treatment should be initiated with a single-pill combination (SPC) of two drugs to improve the speed, efficiency and predictability of BP control. The aim of the study was to evaluate the treatment of AH with fixed combinations of antihypertensive drugs in three patients with associated comorbidities. The blood pressure target values in these patients were reached only after the use of fixed combinations of antihypertensive drugs in the treatment. The results of the study showed that a combination of two drugs in one pill - an angiotensin II receptor blocker/thiazide diuretic or an angiotensin-converting-enzyme inhibitor/a beta blocker- or three drugs in one pill - an angiotensin-converting enzyme inhibitor/a thiazide-like diuretic/a calcium channel blocker is advantageous and provides effective control of AH. Combined treatment allows the use of lower doses of antihypertensive drugs, improves patient adherence to treatment, and reduces adverse drug effects; as a result blood pressure target values are reached faster. [ABSTRACT FROM AUTHOR]

Background: The aim of this work was to find a reliable nested PCR for the detection of Helicobacter pylori in biopsy, stool, and saliva specimens. Materials and Methods: Novel nested PCR was elaborated and validated on 81 clinical biopsy, stool, and saliva samples from the same individual and compared to available H pylori assays: histology, rapid urease test (RUT), stool antigen test (SAT), 13C‐urea breath test (UBT). Results: The efficiency and selectivity of 17 published nested polymerase chain reactions (PCR) available for Helicobacter pylori detection were re‐evaluated. Most of them had serious limitations and mistakes in primer design. Hence, we elaborated a nested PCR for the unambiguous identification of H pylori in biopsy, stool, and saliva, using primers targeted to variable regions of the 16S ribosomal RNA (rRNA) gene. Moreover, we determined the detection limit by adding a known number of cells. This number was as low as 0.5 cells in a PCR vial, but due to the DNA isolation procedures, it required 1‐5 × 103 cells/g or ml of specimen. The sensitivity for nested PCR from stomach biopsies was on the same scale as 13C‐UBT (93.8%), but it was much lower in amplifications from stool (31.3%). Sequencing of all obtained PCR products exclusively confirmed H pylori‐specific DNA sequences. Conclusions: Elaborated nested PCR assay can serve as an auxiliary method for controversial samples (patients with bleeding or taking proton‐pump inhibitor) in laboratories with basic equipment. The sensitivity and specificity for the amplification from gastric biopsies was almost like 13C‐UBT. Despite the good sensitivity, the threshold occurrence and the ability to survive in the oral cavity aside from and independent of the stomach is the reason why H pylori DNA cannot be reliably detected in saliva, stool, and some biopsy samples. [ABSTRACT FROM AUTHOR]

7H-Dibenzo[ c, g]carbazole (DBC) is a heterocyclic aromatic hydrocarbon that is carcinogenic in many species and tissues. DBC is a common environmental pollutant, and is therefore constantly exposed to sunlight. However, there are limited data exploring the toxicity of DBC photoexcitation products. Here, we investigated the impact of ultraviolet (UV) A radiation on the biological activity of DBC and its methyl derivatives, 5, 9-dibenzo[ c, g]carbazole and N-methyl dibenzo[ c, g]carbazole, on human skin HaCaT keratinocytes. Co-exposure of HaCaT cells to UVA and DBC derivatives resulted in a sharp dose-dependent decrease in cell survival and apparent changes in cell morphology. Under the same treatment conditions, significant increases in DNA strand breaks, intracellular reactive oxygen species, and oxidative damage to DNA were observed in HaCaT cells. Consistent with these results, an apparent inhibition in superoxide dismutase, but not glutathione peroxidase activity, was detected in cells treated with DBC and its derivatives under UVA irradiation. The photoactivation-induced toxicity of individual DBC derivatives correlated with the electron excitation energies approximately expressed as the energy difference between the highest occupied and the lowest vacant molecular orbital. Our data provide the first evidence that UVA can enhance the toxicity of DBC and its derivatives. Photoactivation-induced conversion of harmless chemical compounds to toxic photoproducts associated with reactive oxygen species generation may substantially amplify the adverse health effects of UVA radiation and contribute to increased incidence of skin cancer. Environ. Mol. Mutagen. 56:388-403, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]