Toxicological Characteristics of Bacterial Nanocellulose in an In Vivo Experiment-Part 1: The Systemic Effects.

Bacterial nanocellulose (BNC) is being considered as a potential replacement for microcrystalline cellulose as a food additive and a source of dietary fiber due to its unique properties. However, studies on the risks of consuming BNC in food are limited, and it is not yet approved for use in food in the US, EU, and Russia. AIM: This study aims to perform a toxicological and hygienic assessment of the safety of BNC in a subacute 8-week administration in rats. METHODS: BNC was administered to male Wistar rats in doses of 0, 1.0, 10.0, and 100 mg/kg body weight for 8 weeks. Various parameters such as anxiety levels, cognitive function, organ masses, blood serum and liver biochemistry, oxidative stress markers, vitamin levels, antioxidant gene expression, and liver and kidney histology were evaluated. RESULTS: Low and medium doses of BNC increased anxiety levels and liver glutathione, while high doses led to elevated LDL cholesterol, creatinine, and uric acid levels. Liver tissue showed signs of degeneration at high doses. BNC did not significantly affect vitamin levels. CONCLUSION: The adverse effects of BNC are either not dose-dependent or fall within normal physiological ranges. Any effects on rats are likely due to micronutrient deficiencies or impacts on intestinal microbiota.

Effect of meso-substituents and medium properties on the photo- and pH-stability, penetration efficiency into bacterial and microscopic fungi cells of terpene-BODIPY conjugates.

In order to expand the arsenal of tools and areas for practical use of BODIPY dyes as bifunctional fluorescent theranostics, we studied the effect of the meso-substituents nature and medium properties on photo- and pH-stability, efficiency of singlet oxygen generation, and affinity to biostructures of terpene-BODIPY conjugates. The BODIPYs fused with myrtenol or thiotherpenoid via carboxylic acid residues exhibit high stability over a wide pH range and the presence of a bulky substituent at the meso-position of BODIPY conjugates increases their photostability two-fold compared to structurally related meso-unsubstituted analogues. Furthermore, the photodegradation rate of the conjugates directly depends on their ability to generate singlet oxygen and the course probability of the corresponding red-ox reactions involving reactive oxygen species. The conjugate of BODIPY with a thiotherpenoid demonstrated high ability to penetrate the membranes of filamentous and yeast-like fungi and bind to membrane of organelles in the fungal cell. At the same time, this compound also had a high ability to penetrate into biofilms of Staphylococcus aureus and Klebsiella pneumoniae and into bacterial cells within the matrix, which makes this compound promising for staining intracellular structures of eukaryotic cells and bacteria embedded into biofilms.

Increasing the Efficacy of Treatment of Staphylococcus aureus-Candida albicans Mixed Infections with Myrtenol.

Infectious diseases caused by various nosocomial microorganisms affect worldwide both immunocompromised and relatively healthy persons. Bacteria and fungi have different tools to evade antimicrobials, such as hydrolysis damaging the drug, efflux systems, and the formation of biofilm that significantly complicates the treatment of the infection. Here, we show that myrtenol potentiates the antimicrobial and biofilm-preventing activity of conventional drugs against S. aureus and C. albicans mono- and dual-species cultures. In our study, the two optical isomers, (-)-myrtenol and (+)-myrtenol, have been tested as either antibacterials, antifungals, or enhancers of conventional drugs. (+)-Myrtenol demonstrated a synergistic effect with amikacin, fluconazole, and benzalkonium chloride on 64-81% of the clinical isolates of S. aureus and C. albicans, including MRSA and fluconazole-resistant fungi, while (-)-myrtenol increased the properties of amikacin and fluconazole to repress biofilm formation in half of the S. aureus and C. albicans isolates. Furthermore, myrtenol was able to potentiate benzalkonium chloride up to sixteen-fold against planktonic cells in an S. aureus-C. albicans mixed culture and repressed the adhesion of S. aureus. The mechanism of both (-)-myrtenol and (+)-myrtenol synergy with conventional drugs was apparently driven by membrane damage since the treatment with both terpenes led to a significant drop in membrane potential similar to the action of benzalkonium chloride. Thus, due to the low toxicity of myrtenol, it seems to be a promising agent to increase the efficiency of the treatment of infections caused by bacteria and be fungi of the genus Candida as well as mixed fungal-bacterial infections, including resistant strains.

Design, Spectral Characteristics, Photostability, and Possibilities for Practical Application of BODIPY FL-Labeled Thioterpenoid.

This paper presents the design and a comparative analysis of the structural and solvation factors on the spectral and biological properties of the BODIPY biomarker with a thioterpene fragment. Covalent binding of the thioterpene moiety to the butanoic acid residue of meso-substituted BODIPY was carried out to find out the membranotropic effect of conjugate to erythrocytes, and to assess the possibilities of its practical application in bioimaging. The molecular structure of the conjugate was confirmed via X-ray, UV/vis-, NMR-, and MS-spectra. It was found that dye demonstrates high photostability and high fluorescence quantum yield (to ~100%) at 514-519 nm. In addition, the marker was shown to effectively penetrate the erythrocytes membrane in the absence of erythrotoxicity. The conjugation of BODIPY with thioterpenoid is an excellent way to increase affinity dyes to biostructures, including blood components.

BODIPY Conjugates as Functional Compounds for Medical Diagnostics and Treatment.

Fluorescent dyes absorbing and emitting in the visible and near-IR regions are promising for the development of fluorescent probes for labeling and bio-visualization of body cells. The ability to absorb and emit in the long-wavelength region increases the efficiency of recording the spectral signals of the probes due to the higher permeability of the skin layers. Compared to other fluorescent dyes, BODIPYs are attractive due to their excellent photophysical properties-narrow absorption and emission, intense fluorescence, simple signal modulation for the practical applications. As part of conjugates with biomolecules, BODIPY could act as a biomarker, but as therapeutic agent, which allows solving several problems at once-labeling or bioimaging and treatment based on the suppression of pathogenic microflora and cancer cells, which provides a huge potential for practical application of BODIPY conjugates in medicine. The review is devoted to the discussion of the recent, promising directions of BODIPY application in the field of conjugation with biomolecules. The first direction is associated with the development of BODIPY conjugates with drugs, including compounds of platinum, paclitaxel, chlorambucil, isoxazole, capsaicin, etc. The second direction is devoted to the labeling of vitamins, hormones, lipids, and other biomolecules to control the processes of their transport, localization in target cells, and metabolism. Within the framework of the third direction, the problem of obtaining functional optically active materials by conjugating BODIPY with other colored and fluorescent particles, in particular, phthalocyanines, is being solved.

Conjugate of meso-carboxysubstituted-BODIPY with thioterpenoid as an effective fluorescent probe: Synthesis, structure, spectral characteristics, and molecular docking.

This paper is devoted to the design of a fluorescent probe based on meso-carboxysubstituted-BODIPY with a thioterpene fragment. The functional replacement of the methoxy group in the BODIPY molecule on a thioterpene fragment was carried out in order to find out the antiplatelet and anticoagulant action mechanisms of thioterpenoids and to assess the membrane and receptor factors contributions. The molecular structure of the conjugate was confirmed via UV/vis-, NMR- and MS-spectra. It is found that the probe is a high fluorescence quantum yield (to âˆ¼ 100%) in the blue-green region at 509-516 nm. Molecular docking of all studied molecules showed that the BODIPY with terpenoid conjugation is an excellent way to increase their affinity to platelet receptor P2Y12.

Lipoic Acid Exacerbates Oxidative Stress and Lipid Accumulation in the Liver of Wistar Rats Fed a Hypercaloric Choline-Deficient Diet.

Non-alcoholic fatty liver disease (NAFLD) is currently estimated as the most prevalent chronic liver disease in all age groups. An increasing body of evidence obtained in experimental and clinical data indicates that oxidative stress is the most important pathogenic factor in the development of NAFLD. The study aimed to investigate the impact of α-lipoic acid (LA), widely used as an antioxidant, on the effects of a hypercaloric choline-deficient diet. Male Wistar rats were divided into three groups: control diet (C); hypercaloric choline-deficient diet (HCCD), and hypercaloric choline-deficient diet with α-lipoic acid (HCCD+LA). Supplementation of HCCD with LA for eight weeks led to a decrease in visceral adipose tissue/body weight ratio, the activity of liver glutathione peroxidase and paraoxonase-1, plasma, and liver total antioxidant activity, as well as an increase in liver/body weight ratio, liver total lipid and triglyceride content, and liver transaminase activities compared to the HCCD group without LA. In conclusion, our study shows that α-lipoic acid detains obesity development but exacerbates the severity of diet-induced oxidative stress and lipid accumulation in the liver of male Wistar rats fed a hypercaloric choline-deficient diet.

Detrimental effects of 6 months exposure to very low doses of a mixture of six pesticides associated with chronic vitamin deficiency on rats.

This study aimed to evaluate the long-term low-dose effects of exposure to a mixture of 6 pesticide active substances (diquat, imazamox, imazethapyr, tepraloxydin, bentazone, acifluorfen) and to elucidate if chronic vitamin deficiency can influence their toxicity. Two hundred Wistar rats were divided in 4 groups: a vitamin-sufficiency control group, a vitamin-deficiency control group, a vitamin sufficiency test group and a vitamin-deficiency test group. The test groups were treated with the aforementioned pesticides at doses 100 times lower than the corresponding NOAEL. After 6 months, ten rats from each group were sacrificed and a complete evaluation of blood and urine biochemistry, biomarkers of oxidative stress, xenobiotic detoxification enzymes and lysosomal enzymes and organ histopathology was performed. The pesticides mixture and vitamin deficiency determined an increase in alkaline phosphatase levels and urinary calcium levels, abnormal serum lipid profile, and a decrease of total blood proteins levels, red blood cells, haematocrit and haemoglobin. The combination of the two stressors up-regulated CYP1A1, CYP1A2, CYP2B1 and GST levels. This study provides a new proof for the need to move forward from single chemical testing to a more complex approach to account for the multitude of stressors that can challenge the setting of real safety levels.

A New «off-on¼ Fluorescence Zinc Ion Sensors Based on Iodo- and Bromosubstituted Dipyrromethenes.

Monoiodo- and dibromsubstituted dipyrromethenes HL1 - HL3 were described as a highly sensitive and selective «Off-On¼ fluorescent chemosensor for Zn2+ based on the chelation-enhanced fluorescence (CHEF) effect. Сoordination reactions of HL1 - HL3 with Zn2+ cations are accompanied by a significant (124 to 215-fold) increase in fluorescence intensity against the background of other metal ions in the binary propanol-1/cyclohexane mixture (1:30). The fluorometric detection limit of Zn2+ ions using HL1 - HL3 sensors is from 3.0∙10-8 to 3.3·10-9 mol/L. The presence of Na+, K+, Ca2+, Mg2+, Mn2+, Ni2+, Co2+, Pb2+ cations does not interfere with the detection of Zn2+. Complexation reactions are accompanied by a visual change in the color of the solution from yellow-orange to pink-raspberry so that the HL1 - HL3 ligands can also be used as a «naked-eye¼ indicators of the presence of Zn2+ ions.

Design, Spectral Characteristics, and Possibilities for Practical Application of BODIPY FL-Labeled Monoterpenoid.

This article describes the design and biological properties of a BODIPY FL-labeled monoterpenoid BF2-meso-(4-((1″R)-6″,6″-dimethylbicyclo[3.1.1]hept-2″-ene-2″)yl-methoxycarbonylpropyl)-3,3',5,5'-tetramethyl-2,2'-dipyrromethene conjugate (BODIPYmyrt). The fluorophore was characterized using X-ray, NMR, MS, and UV/vis spectroscopy. The conjugate exhibits a high quantum yield (to ∼100%) in the region 515-518 nm. BODIPYmyrt effectively penetrates the membranes of the bacterial and fungal cells and therefore can be used to examine the features of a broad spectrum of Gram-positive and Gram-negative bacteria and pathogenic fungi as well. Moreover, BODIPYmyrt exhibits a moderate tropism to the subcellular structures in mammalian cells (e.g., mitochondria), thereby providing an attractive scaffold for fluorophores to examine these particular organelles.

Spectroscopic and In Vitro Investigations of Boron(III) Complex with Meso-4-Methoxycarbonylpropylsubstituted Dipyrromethene for Fluorescence Bioimaging Applications.

This study focuses on the behavior of a new fluorescent marker for labeling individual biomolecules and staining cell organelles developed on a meso-substituted BODIPY platform. Boron(III) complex with meso-4-methoxycarbonylpropylsubstituted 3,3',5,5'-tetramethyl-2,2'-dipyrromethene has been synthesized and identified via visible, UV-, NMR- and MS-spectra X-ray. The behavior of fluorophore in solutions has been studied with various experimental techniques. It has been found that luminophore exhibits a high quantum yield (almost ~100-75%) in the blue-green region (513-520 nm) and has high photostability. In addition, biological analysis indicates that the fluorophore exhibits a tendency to effectively penetrate into cell membranes. On the other hand, the proposed BODIPY can be used to study the significant differences among a large number of pathogens of mycotic infections, as well as to visualize structural changes in the plasma membrane, which is necessary for the clearance of mammalian cells undergoing apoptotic cell death.

Novel Zinc(II) Bis(Dipyrromethenate)-Doped Ethyl Cellulose Sensors for Acetone Vapor Fluorescence Detection.

In this paper, we report on the results of spectrofluorimetric study of new fluorescent sensor based on [Zn2L2] doped in ethyl cellulose. The sensor optical signal is based on the rapid fluorescence quenching in the presence of acetone vapor. The acetone vapor detection limit in a gas mixture by means of sensor based on [Zn2L2] doped in ethyl cellulose is 1.68 ppb. Being highly sensitive to the acetone acetone presence, instant in response and easy to use, the sensor can find an application for the noninvasive diagnostics of diabetes as well as for the monitoring of the content of acetone acetone in the air at industrial and laboratory facilities. Graphical Abstract.

The high sensitive and selective "off-on" fluorescent Zn2+ sensor based on the Bis(2,4,7,8,9-pentamethyldipyrrolylmethene-3-yl)methane.

A fluorescent chemosensor based on the 3,3'-bis(dipyrrin) bearing two chromophoric dipyrrin units was synthesized, which showed a strongly enhanced fluorescent intensity in the presence of Zn(2+) ions and a high selectivity toward Zn(2+) ions over a wide range of tested metal ions in organic solvents.

Activity of xenobiotic-metabolizing enzymes in the liver of rats with multi-vitamin deficiency.

The purpose of the study was to determine how multi-vitamin deficiency affects xenobiotic-metabolizing enzyme (XME) activities in the rat liver. Vitamin levels and XME activities were studied in the livers of male Wistar rats who were fed for 4 weeks with semi-synthetic diets containing either adequate (100 % of recommended vitamin intake) levels of vitamins (control), or decreased vitamin levels (50 % or 20 % of recommended vitamin intake). The study results have shown that moderate vitamin deficiency (50 %) leads to a decrease of vitamin A levels only, and to a slight increase, as compared with the control, in the following enzyme activities: methoxyresorufin O-dealkylase (MROD) activity of CYP1 A2 - by 34 % (p < 0.05), UDP-glucuronosyl transferase - by 26 % (p < 0.05), and quinone reductase - by 55 % (p < 0.05). Profound vitamin deficiency (20 %) led to a decrease of vitamins A, E, B1, B2, and C, and enzyme activities in the liver: MROD - to 78 % of the control level (p < 0.05), 4-nitrophenol hydroxylase - to 74 % (p < 0.05), heme oxygenase-1 - to 83 % (p < 0.05), and quinone reductase - to 60 % (p < 0.05). At the same time, the UDP-glucuronosyl transferase activity and ethoxyresorufin O-dealkylase activity of CYP1A1, pentoxyresorufin O-dealkylase activity of CYP2B1/2 and 6ß-testosterone hydroxylase, as well as the total activity of glutathione transferase did not differ from the control levels. The study has demonstrated that profound multi-vitamin deficiency is associated with a decrease in the expression of CYP1A2 and CYP3A1 mRNAs to 62 % and 79 %, respectively. These data indicated that a short-term but profound multi-vitamin deficiency in rats leads to a decrease in the activities and expression of the some XME that play an important role in detoxification of xenobiotics and metabolism of drugs and antioxidant protection.