Research

14 pages, 3847 KiB

Open AccessArticle

Antimicrobial Ionic Liquids: Ante-Mortem Mechanisms of Pathogenic EPEC and MRSA Examined by FTIR Spectroscopy

by Patrick Mikuni-Mester, Christian Robben, Anna K. Witte, Kristina Linke, Monika Ehling-Schulz, Peter Rossmanith and Tom Grunert

Int. J. Mol. Sci. 2024, 25(9), 4705; https://doi.org/10.3390/ijms25094705 - 26 Apr 2024

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Abstract

Ionic liquids (ILs) have gained considerable attention due to their versatile and designable properties. ILs show great potential as antibacterial agents, but understanding the mechanism of attack on bacterial cells is essential to ensure the optimal design of IL-based biocides. The final aim [...] Read more.

Ionic liquids (ILs) have gained considerable attention due to their versatile and designable properties. ILs show great potential as antibacterial agents, but understanding the mechanism of attack on bacterial cells is essential to ensure the optimal design of IL-based biocides. The final aim is to achieve maximum efficacy while minimising toxicity and preventing resistance development in target organisms. In this study, we examined a dose–response analysis of ILs’ antimicrobial activity against two pathogenic bacteria with different Gram types in terms of molecular responses on a cellular level using Fourier-transform infrared (FTIR) spectroscopy. In total, 18 ILs with different antimicrobial active motifs were evaluated on the Gram-negative enteropathogenic Escherichia coli (EPEC) and Gram-positive methicillin-resistant Staphylococcus aureus (MRSA). The results showed that most ILs impact bacterial proteins with increasing concentration but have a minimal effect on cellular membranes. Dose–response spectral analysis revealed a distinct ante-mortem response against certain ILs for MRSA but not for EPEC. We found that at sub-lethal concentrations, MRSA actively changed their membrane composition to counteract the damaging effect induced by the ILs. This suggests a new adaptive mechanism of Gram-positive bacteria against ILs and demonstrates the need for a better understanding before using such substances as novel antimicrobials. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Toxic and Activated Effects of Exogenous Compounds)

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19 pages, 1875 KiB

Open AccessArticle

Effects of Endohedral Gd-Containing Fullerenols with a Different Number of Oxygen Substituents on Bacterial Bioluminescence

by Evsei A. Stepin, Ekaterina S. Sushko, Natalia G. Vnukova, Grigoriy N. Churilov, Anastasia V. Rogova, Felix N. Tomilin and Nadezhda S. Kudryasheva

Int. J. Mol. Sci. 2024, 25(2), 708; https://doi.org/10.3390/ijms25020708 - 05 Jan 2024

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Abstract

Gadolinium (Gd)-containing fullerenols are perspective agents for magnetic resonance imaging and cancer research. They combine the unique paramagnetic properties of Gd with solubility in water, low toxicity and antiradical activity of fullerenols. We compared the bioeffects of two Gd-containing fullerenols with a different [...] Read more.

Gadolinium (Gd)-containing fullerenols are perspective agents for magnetic resonance imaging and cancer research. They combine the unique paramagnetic properties of Gd with solubility in water, low toxicity and antiradical activity of fullerenols. We compared the bioeffects of two Gd-containing fullerenols with a different number of oxygen groups—20 and 42: Gd@C₈₂O₂₀H₁₄ and Gd@C₈₂O₄₂H₃₂. The bioluminescent bacteria-based assay was applied to monitor the toxicity of fullerenols, bioluminescence was applied as a signal physiological parameter, and bacterial enzyme-based assay was used to evaluate the fullerenol effects on enzymatic intracellular processes. Chemiluminescence luminol assay was applied to monitor the content of reactive oxygen species (ROS) in bacterial and enzymatic media. It was shown that Gd@C₈₂O₄₂H₃₂ and Gd@C₈₂O₂₀H₁₄ inhibited bacterial bioluminescence at >10⁻¹ and >10⁻² gL⁻¹, respectively, revealing a lower toxicity of Gd@C₈₂O₄₂H₃₂. Low-concentration (10⁻³–10⁻¹ gL⁻¹) bacterial bioluminescence activation by Gd@C₈₂O₄₂H₃₂ was observed, while this activation was not found under exposure to Gd@C₈₂O₂₀H₁₄. Additional carboxyl groups in the structure of Gd@C₈₂O₄₂H₃₂ were determined by infrared spectroscopy and confirmed by quantum chemical calculations. The groups were supposed to endow Gd@C₈₂O₄₂H₃₂ with higher penetration ability through the cellular membrane, activation ability, lower toxicity, balancing of the ROS content in the bacterial suspensions, and lower aggregation in aqueous media. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Toxic and Activated Effects of Exogenous Compounds)

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16 pages, 2987 KiB

Open AccessArticle

High-Throughput Transcriptomics Differentiates Toxic versus Non-Toxic Chemical Exposures Using a Rat Liver Model

by Venkat R. Pannala and Anders Wallqvist

Int. J. Mol. Sci. 2023, 24(24), 17425; https://doi.org/10.3390/ijms242417425 - 13 Dec 2023

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Abstract

To address the challenge of limited throughput with traditional toxicity testing, a newly developed high-throughput transcriptomics (HTT) platform, together with a 5-day in vivo rat model, offers an alternative approach to estimate chemical exposures and provide reasonable estimates of toxicological endpoints. This study [...] Read more.

To address the challenge of limited throughput with traditional toxicity testing, a newly developed high-throughput transcriptomics (HTT) platform, together with a 5-day in vivo rat model, offers an alternative approach to estimate chemical exposures and provide reasonable estimates of toxicological endpoints. This study contains an HTT analysis of 18 environmental chemicals with known liver toxicity. They were evaluated using male Sprague Dawley rats exposed to various concentrations daily for five consecutive days via oral gavage, with data collected on the sixth day. Here, we further explored the 5-day rat model to identify potential gene signatures that can differentiate between toxic and non-toxic liver responses and provide us with a potential histopathological endpoint of chemical exposure. We identified a distinct gene expression pattern that differentiated non-hepatotoxic compounds from hepatotoxic compounds in a dose-dependent manner, and an analysis of the significantly altered common genes indicated that toxic chemicals predominantly upregulated most of the genes and several pathways in amino acid and lipid metabolism. Finally, our liver injury module analysis revealed that several liver-toxic compounds showed similarities in the key injury phenotypes of cellular inflammation and proliferation, indicating potential molecular initiating processes that may lead to a specific end-stage liver disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Toxic and Activated Effects of Exogenous Compounds)

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16 pages, 4286 KiB

Open AccessArticle

Plant Secondary Compounds Promote White Adipose Tissue Browning via Modulation of the Gut Microbiota in Small Mammals

by Shien Ren, Liangzhi Zhang, Xianjiang Tang, Chao Fan, Yaqi Zhao, Qi Cheng and Yanming Zhang

Int. J. Mol. Sci. 2023, 24(24), 17420; https://doi.org/10.3390/ijms242417420 - 13 Dec 2023

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Abstract

The browning of white adipose tissue (WAT) is a promising area of research for treating metabolic disorders and obesity in the future. However, studies on plant secondary compounds promoting WAT browning are limited. Herein, we explored the effects of swainsonine (SW) on gut [...] Read more.

The browning of white adipose tissue (WAT) is a promising area of research for treating metabolic disorders and obesity in the future. However, studies on plant secondary compounds promoting WAT browning are limited. Herein, we explored the effects of swainsonine (SW) on gut microbiota and WAT browning in captive pikas. SW inhibited body mass gain, increased brown adipose tissue (BAT) mass, and induced WAT browning in pikas. The 16S rDNA sequencing revealed a significant reduction in the alpha diversity and altered community structure of the gut microbiota in captive pikas. However, the addition of SW to the diet significantly increased the alpha diversity of gut microbiota and the relative abundance of Akkermansia, Prevotella, and unclassified_f__Lachnospiraceae, along with the complexity of the microbial co-occurrence network structure, which decreased in the guts of captive pikas. Functional profiles showed that SW significantly decreased the relative abundances of energy metabolism, lipid metabolism, and glycan biosynthesis and metabolism, which were enriched in captive pikas. Furthermore, SW decreased deterministic processes of gut microbiota assembly in July and increased them in November. Finally, the genera Prevotella and unclassified_f__Prevotellaceae were positively correlated with BAT mass. Our results highlighted that plant secondary compounds promote WAT browning by modulating the gut microbiota in small mammals. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Toxic and Activated Effects of Exogenous Compounds)

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31 pages, 2853 KiB

Open AccessArticle

Mitochondrial and Proteasome Dysfunction Occurs in the Hearts of Mice Treated with Triazine Herbicide Prometryn

by Rasheed O. Sule, Brett S. Phinney, Michelle R. Salemi and Aldrin V. Gomes

Int. J. Mol. Sci. 2023, 24(20), 15266; https://doi.org/10.3390/ijms242015266 - 17 Oct 2023

Viewed by 972

Abstract

Prometryn is a methylthio-s-triazine herbicide used to control the growth of annual broadleaf and grass weeds in many cultivated plants. Significant traces of prometryn are documented in the environment, mainly in waters, soil, and plants used for human and domestic consumption. Previous studies [...] Read more.

Prometryn is a methylthio-s-triazine herbicide used to control the growth of annual broadleaf and grass weeds in many cultivated plants. Significant traces of prometryn are documented in the environment, mainly in waters, soil, and plants used for human and domestic consumption. Previous studies have shown that triazine herbicides have carcinogenic potential in humans. However, there is limited information about the effects of prometryn on the cardiac system in the literature, or the mechanisms and signaling pathways underlying any potential cytotoxic effects are not known. It is important to understand the possible effects of exogenous compounds such as prometryn on the heart. To determine the mechanisms and signaling pathways affected by prometryn (185 mg/kg every 48 h for seven days), we performed proteomic profiling of male mice heart with quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) using ten-plex tandem mass tag (TMT) labeling. The data suggest that several major pathways, including energy metabolism, protein degradation, fatty acid metabolism, calcium signaling, and antioxidant defense system were altered in the hearts of prometryn-treated mice. Proteasome and immunoproteasome activity assays and expression levels showed proteasome dysfunction in the hearts of prometryn-treated mice. The results suggest that prometryn induced changes in mitochondrial function and various signaling pathways within the heart, particularly affecting stress-related responses. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Toxic and Activated Effects of Exogenous Compounds)

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9 pages, 2152 KiB

Open AccessCommunication

Kinetic Intricacies of the Light Emission and Antiradical Influence of Exogenous Bioantioxidants Transformation Products in the Chemiluminescence Bioantioxidant Assay

by Vladimir V. Naumov, Aleksei V. Trofimov, Galina F. Fedorova, Olga I. Yablonskaya and Rostislav F. Vasil’ev

Int. J. Mol. Sci. 2023, 24(10), 8486; https://doi.org/10.3390/ijms24108486 - 09 May 2023

Cited by 1 | Viewed by 879

Abstract

The subject matter of the reported work refers to studying the interactions followed by the excited-state generation, which are chemical models of oxidative processes leading to a weak light emission emerging from living cells, and to explore the possibilities of using them as [...] Read more.

The subject matter of the reported work refers to studying the interactions followed by the excited-state generation, which are chemical models of oxidative processes leading to a weak light emission emerging from living cells, and to explore the possibilities of using them as tools for evaluating the activity of oxygen-metabolism modulators, most prominently, natural bioantioxidants of biomedical value in particular. Methodologically, major attention is paid to analyzing the shapes of the time profiles of the light emission derived from a model sensory system in the presence of lipid samples of vegetable and animal (fish) origin rich in bioantioxidants. As a result, a modified reaction mechanism involving 12 elementary steps is proposed to rationalize the light-emission kinetics in the presence of natural bioantioxidants. We conclude that free radicals formed from bioantioxidants and their dimerization products contribute significantly to the general antiradical activity of lipid samples, which should be taken into account in developing efficient bioantioxidant assays for biomedical applications and while establishing the mechanisms of bioantioxidant effects on metabolic processes in vivo. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Toxic and Activated Effects of Exogenous Compounds)

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22 pages, 3952 KiB

Open AccessArticle

Enzyme Inhibition-Based Assay to Estimate the Contribution of Formulants to the Effect of Commercial Pesticide Formulations

by Elena N. Esimbekova, Valeriya P. Kalyabina, Kseniya V. Kopylova, Victoria I. Lonshakova-Mukina, Anna A. Antashkevich, Irina G. Torgashina, Kirill A. Lukyanenko, Elena V. Nemtseva and Valentina A. Kratasyuk

Int. J. Mol. Sci. 2023, 24(3), 2268; https://doi.org/10.3390/ijms24032268 - 23 Jan 2023

Cited by 2 | Viewed by 2229

Abstract

Pesticides can affect the health of individual organisms and the function of the entire ecosystem. Therefore, thorough assessment of the risks associated with the use of pesticides is a high-priority task. An enzyme inhibition-based assay is used in this study as a convenient [...] Read more.

Pesticides can affect the health of individual organisms and the function of the entire ecosystem. Therefore, thorough assessment of the risks associated with the use of pesticides is a high-priority task. An enzyme inhibition-based assay is used in this study as a convenient and quick tool to study the effects of pesticides at the molecular level. The contribution of formulants to toxicological properties of the pesticide formulations has been studied by analyzing effects of 7 active ingredients of pesticides (AIas) and 10 commercial formulations based on them (AIfs) on the function of a wide range of enzyme assay systems differing in complexity (single-, coupled, and three-enzyme assay systems). Results have been compared with the effects of AIas and AIfs on bioluminescence of the luminous bacterium Photobacterium phosphoreum. Mostly, AIfs produce a considerably stronger inhibitory effect on the activity of enzyme assay systems and bioluminescence of the luminous bacterium than AIas, which confirms the contribution of formulants to toxicological properties of the pesticide formulation. Results of the current study demonstrate that “inert” ingredients are not ecotoxicologically safe and can considerably augment the inhibitory effect of pesticide formulations; therefore, their use should be controlled more strictly. Circular dichroism and fluorescence spectra of the enzymes used for assays do not show any changes in the protein structure in the presence of commercial pesticide formulations during the assay procedure. This finding suggests that pesticides produce the inhibitory effect on enzymes through other mechanisms. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Toxic and Activated Effects of Exogenous Compounds)

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10 pages, 2043 KiB

Open AccessCommunication

Toxicity of Different Types of Surfactants via Cellular and Enzymatic Assay Systems

by Oleg S. Sutormin, Elizaveta M. Kolosova, Irina G. Torgashina, Valentina A. Kratasyuk, Nadezhda S. Kudryasheva, Julia S. Kinstler and Devard I. Stom

Int. J. Mol. Sci. 2023, 24(1), 515; https://doi.org/10.3390/ijms24010515 - 28 Dec 2022

Cited by 3 | Viewed by 2269

Abstract

Surfactants have a widespread occurrence, not only as household detergents, but also in their application in industry and medicine. There are numerous bioassays for assessing surfactant toxicity, but investigations of their impact on biological systems at the molecular level are still needed. In [...] Read more.

Surfactants have a widespread occurrence, not only as household detergents, but also in their application in industry and medicine. There are numerous bioassays for assessing surfactant toxicity, but investigations of their impact on biological systems at the molecular level are still needed. In this paper, luminous marine bacteria and their coupled NAD(P)H:FMN-oxidoreductase + luciferase (Red + Luc) enzyme system was applied to examine the effects of different types of surfactants, including cationic cetyltrimethylammonium bromide (CTAB), non-ionic polyoxyethylene 20 sorbitan monooleate (Tween 80) and anionic sodium lauryl sulfate (SLS), and to assess whether the Red + Luc enzyme system can be used as a more sensitive indicator of toxicity. It was shown that the greatest inhibitory effect of the surfactants on the activity of luminous bacteria and the Red + Luc enzyme system was in the presence of SLS samples. The calculated IC₅₀ and EC₅₀ values of SLS were 10⁻⁵ M and 10⁻² M for the enzymatic and cellular assay systems, respectively. The results highlight the benefits of using the enzymatic assay system in ecotoxicology as a tool for revealing surfactant effects on intracellular proteins if the cellular membrane is damaged under a long-term exposure period in the presence of the surfactants. For this purpose, the bioluminescent enzyme-inhibition-based assay could be used as an advanced research tool for the evaluation of surfactant toxicity at the molecular level of living organisms due to its technical simplicity and rapid response time. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Toxic and Activated Effects of Exogenous Compounds)

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23 pages, 3151 KiB

Open AccessArticle

Differences in the Formation of Reactive Oxygen Species and Their Cytotoxicity between Thiols Combined with Aqua- and Cyanocobalamins

by Yuri V. Shatalin, Victoria S. Shubina, Marina E. Solovieva and Vladimir S. Akatov

Int. J. Mol. Sci. 2022, 23(19), 11032; https://doi.org/10.3390/ijms231911032 - 20 Sep 2022

Cited by 2 | Viewed by 1623

Abstract

Cobalamin is an essential nutrient required for the normal functioning of cells. Its deficiency can lead to various pathological states. Hydroxocobalamin (HOCbl) and cyanocobalamin (CNCbl) are the forms of vitamin B12 that are most commonly used for supplementation. There is substantial evidence indicating [...] Read more.

Cobalamin is an essential nutrient required for the normal functioning of cells. Its deficiency can lead to various pathological states. Hydroxocobalamin (HOCbl) and cyanocobalamin (CNCbl) are the forms of vitamin B12 that are most commonly used for supplementation. There is substantial evidence indicating that cobalamins can both suppress and promote oxidative stress; however, the mechanisms underlying these effects are poorly understood. Here, it was shown that the oxidation of thiols catalyzed by HOCbl and CNCbl is accompanied by reactive oxygen species (ROS) production and induces, under certain conditions, oxidative stress and cell death. The form of vitamin B12 and the structure of thiol play a decisive role in these processes. It was found that the mechanisms and kinetics of thiol oxidation catalyzed by HOCbl and CNCbl differ substantially. HOCbl increased the rate of oxidation of thiols to a greater extent than CNCbl, but quenched ROS in combination with certain thiols. Oxidation catalyzed by CNCbl was generally slower. Yet, the absence of ROS quenching resulted in their higher accumulation. The aforementioned results might explain a more pronounced cytotoxicity induced by combinations of thiols with CNCbl. On the whole, the data obtained provide a new insight into the redox processes in which cobalamins are involved. Our results might also be helpful in developing new approaches to the treatment of some cobalamin-responsive disorders in which oxidative stress is an important component. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Toxic and Activated Effects of Exogenous Compounds)

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19 pages, 3099 KiB

Open AccessArticle

Synthetic Secoisolariciresinol Diglucoside (LGM2605) Prevents Asbestos-Induced Inflammation and Genotoxic Cell Damage in Human Mesothelial Cells

by Ralph A. Pietrofesa, Shampa Chatterjee, Yuwaraj Kadariya, Joseph R. Testa, Steven M. Albelda and Melpo Christofidou-Solomidou

Int. J. Mol. Sci. 2022, 23(17), 10085; https://doi.org/10.3390/ijms231710085 - 03 Sep 2022

Cited by 2 | Viewed by 1623

Abstract

Although alveolar macrophages play a critical role in malignant transformation of mesothelial cells following asbestos exposure, inflammatory and oxidative processes continue to occur in the mesothelial cells lining the pleura that may contribute to the carcinogenic process. Malignant transformation of mesothelial cells following [...] Read more.

Although alveolar macrophages play a critical role in malignant transformation of mesothelial cells following asbestos exposure, inflammatory and oxidative processes continue to occur in the mesothelial cells lining the pleura that may contribute to the carcinogenic process. Malignant transformation of mesothelial cells following asbestos exposure occurs over several decades; however, amelioration of DNA damage, inflammation, and cell injury may impede the carcinogenic process. We have shown in an in vitro model of asbestos-induced macrophage activation that synthetic secoisolariciresinol diglucoside (LGM2605), given preventively, reduced inflammatory cascades and oxidative/nitrosative cell damage. Therefore, it was hypothesized that LGM2605 could also be effective in reducing asbestos-induced activation and the damage of pleural mesothelial cells. LGM2605 treatment (50 µM) of huma n pleural mesothelial cells was initiated 4 h prior to exposure to asbestos (crocidolite, 20 µg/cm²). Supernatant and cells were evaluated at 0, 2, 4, and 8 h post asbestos exposure for reactive oxygen species (ROS) generation, DNA damage (oxidized guanine), inflammasome activation (caspase-1 activity) and associated pro-inflammatory cytokine release (IL-1β, IL-18, IL-6, TNFα, and HMGB1), and markers of oxidative stress (malondialdehyde (MDA) and 8-iso-prostaglandin F2a (8-iso-PGF2α). Asbestos induced a time-dependent ROS increase that was significantly (p < 0.0001) reduced (29.4%) by LGM2605 treatment. LGM2605 pretreatment also reduced levels of asbestos-induced DNA damage by 73.6% ± 1.0%. Although levels of inflammasome-activated cytokines, IL-1β and IL-18, reached 29.2 pg/mL ± 0.7 pg/mL and 43.9 pg/mL ± 0.8 pg/mL, respectively, LGM2605 treatment significantly (p < 0.0001) reduced cytokine levels comparable to baseline (non-asbestos exposed) values (3.8 pg/mL ± 0.2 pg/mL and 5.4 pg/mL ± 0.2 pg/mL, respectively). Furthermore, levels of IL-6 and TNFα in asbestos-exposed mesothelial cells were high (289.1 pg/mL ± 2.9 pg/mL and 511.3 pg/mL ± 10.2 pg/mL, respectively), while remaining undetectable with LGM2605 pretreatment. HMGB1 (a key inflammatory mediator and initiator of malignant transformation) release was reduced 75.3% ± 0.4% by LGM2605. Levels of MDA and 8-iso-PGF2α, markers of oxidative cell injury, were significantly (p < 0.001) reduced by 80.5% ± 0.1% and 76.6% ± 0.3%, respectively. LGM2605, given preventively, reduced ROS generation, DNA damage, and inflammasome-activated cytokine release and key inflammatory mediators implicated in asbestos-induced malignant transformation of normal mesothelial cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Toxic and Activated Effects of Exogenous Compounds)

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