Research

11 pages, 1127 KiB

Open AccessArticle

Oxidative Stress Reaction to Hypobaric–Hyperoxic Civilian Flight Conditions

by Nikolaus C. Netzer, Heidelinde Jaekel, Roland Popp, Johanna M. Gostner, Michael Decker, Frederik Eisendle, Rachel Turner, Petra Netzer, Carsten Patzelt, Christian Steurer, Marco Cavalli, Florian Forstner and Stephan Pramsohler

Biomolecules 2024, 14(4), 481; https://doi.org/10.3390/biom14040481 - 15 Apr 2024

Viewed by 473

Abstract

Background: In military flight operations, during flights, fighter pilots constantly work under hyperoxic breathing conditions with supplemental oxygen in varying hypobaric environments. These conditions are suspected to cause oxidative stress to neuronal organ tissues. For civilian flight operations, the Federal Aviation Administration (FAA) [...] Read more.

Background: In military flight operations, during flights, fighter pilots constantly work under hyperoxic breathing conditions with supplemental oxygen in varying hypobaric environments. These conditions are suspected to cause oxidative stress to neuronal organ tissues. For civilian flight operations, the Federal Aviation Administration (FAA) also recommends supplemental oxygen for flying under hypobaric conditions equivalent to higher than 3048 m altitude, and has made it mandatory for conditions equivalent to more than 3657 m altitude. Aim: We hypothesized that hypobaric–hyperoxic civilian commercial and private flight conditions with supplemental oxygen in a flight simulation in a hypobaric chamber at 2500 m and 4500 m equivalent altitude would cause significant oxidative stress in healthy individuals. Methods: Twelve healthy, COVID-19-vaccinated (third portion of vaccination 15 months before study onset) subjects (six male, six female, mean age 35.7 years) from a larger cohort were selected to perform a 3 h flight simulation in a hypobaric chamber with increasing supplemental oxygen levels (35%, 50%, 60%, and 100% fraction of inspired oxygen, FiO₂, via venturi valve-equipped face mask), switching back and forth between simulated altitudes of 2500 m and 4500 m. Arterial blood pressure and oxygen saturation were constantly measured via radial catheter and blood samples for blood gases taken from the catheter at each altitude and oxygen level. Additional blood samples from the arterial catheter at baseline and 60% oxygen at both altitudes were centrifuged inside the chamber and the serum was frozen instantly at −21 °C for later analysis of the oxidative stress markers malondialdehyde low-density lipoprotein (M-LDL) and glutathione-peroxidase 1 (GPX1) via the ELISA test. Results: Eleven subjects finished the study without adverse events. Whereas the partial pressure of oxygen (PO₂) levels increased in the mean with increasing oxygen levels from baseline 96.2 mm mercury (mmHg) to 160.9 mmHg at 2500 m altitude and 60% FiO₂ and 113.2 mmHg at 4500 m altitude and 60% FiO₂, there was no significant increase in both oxidative markers from baseline to 60% FiO₂ at these simulated altitudes. Some individuals had a slight increase, whereas some showed no increase at all or even a slight decrease. A moderate correlation (Pearson correlation coefficient 0.55) existed between subject age and glutathione peroxidase levels at 60% FiO₂ at 4500 m altitude. Conclusion: Supplemental oxygen of 60% FiO₂ in a flight simulation, compared to flying in cabin pressure levels equivalent to 2500 m–4500 m altitude, does not lead to a significant increase or decrease in the oxidative stress markers M-LDL and GPX1 in the serum of arterial blood. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

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16 pages, 4179 KiB

Open AccessArticle

Elevated Levels of Mislocalised, Constitutive Ras Signalling Can Drive Quiescence by Uncoupling Cell-Cycle Regulation from Metabolic Homeostasis

by Elliot Piper-Brown, Fiona Dresel, Eman Badr and Campbell W. Gourlay

Biomolecules 2023, 13(11), 1619; https://doi.org/10.3390/biom13111619 - 06 Nov 2023

Viewed by 1118

Abstract

The small GTPase Ras plays an important role in connecting external and internal signalling cues to cell fate in eukaryotic cells. As such, the loss of RAS regulation, localisation, or expression level can drive changes in cell behaviour and fate. Post-translational modifications and [...] Read more.

The small GTPase Ras plays an important role in connecting external and internal signalling cues to cell fate in eukaryotic cells. As such, the loss of RAS regulation, localisation, or expression level can drive changes in cell behaviour and fate. Post-translational modifications and expression levels are crucial to ensure Ras localisation, regulation, function, and cell fate, exemplified by RAS mutations and gene duplications that are common in many cancers. Here, we reveal that excessive production of yeast Ras2, in which the phosphorylation-regulated serine at position 225 is replaced with alanine or glutamate, leads to its mislocalisation and constitutive activation. Rather than inducing cell death, as has been widely reported to be a consequence of constitutive Ras2 signalling in yeast, the overexpression of RAS2^S225A or RAS2^S225E alleles leads to slow growth, a loss of respiration, reduced stress response, and a state of quiescence. These effects are mediated via cAMP/PKA signalling and transcriptional changes, suggesting that quiescence is promoted by an uncoupling of cell-cycle regulation from metabolic homeostasis. The quiescent cell fate induced by the overexpression of RAS2^S225A or RAS2^S225E could be rescued by the deletion of CUP9, a suppressor of the dipeptide transporter Ptr2, or the addition of peptone, implying that a loss of metabolic control, or a failure to pass a metabolic checkpoint, is central to this altered cell fate. Our data suggest that the combination of an increased RAS2 copy number and a dominant active mutation that leads to its mislocalisation can result in growth arrest and add weight to the possibility that approaches to retarget RAS signalling could be employed to develop new therapies. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

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13 pages, 1766 KiB

Open AccessArticle

Effect of mitoTEMPO on Redox Reactions in Different Body Compartments upon Endotoxemia in Rats

by Adelheid Weidinger, Andras T. Meszaros, Sergiu Dumitrescu and Andrey V. Kozlov

Biomolecules 2023, 13(5), 794; https://doi.org/10.3390/biom13050794 - 05 May 2023

Viewed by 1161

Abstract

Mitochondrial ROS (mitoROS) control many reactions in cells. Biological effects of mitoROS in vivo can be investigated by modulation via mitochondria-targeted antioxidants (mtAOX, mitoTEMPO). The aim of this study was to determine how mitoROS influence redox reactions in different body compartments in a [...] Read more.

Mitochondrial ROS (mitoROS) control many reactions in cells. Biological effects of mitoROS in vivo can be investigated by modulation via mitochondria-targeted antioxidants (mtAOX, mitoTEMPO). The aim of this study was to determine how mitoROS influence redox reactions in different body compartments in a rat model of endotoxemia. We induced inflammatory response by lipopolysaccharide (LPS) injection and analyzed effects of mitoTEMPO in blood, abdominal cavity, bronchoalveolar space, and liver tissue. MitoTEMPO decreased the liver damage marker aspartate aminotransferase; however, it neither influenced the release of cytokines (e.g., tumor necrosis factor, IL-4) nor decreased ROS generation by immune cells in the compartments examined. In contrast, ex vivo mitoTEMPO treatment substantially reduced ROS generation. Examination of liver tissue revealed several redox paramagnetic centers sensitive to in vivo LPS and mitoTEMPO treatment and high levels of nitric oxide (NO) in response to LPS. NO levels in blood were lower than in liver, and were decreased by in vivo mitoTEMPO treatment. Our data suggest that (i) inflammatory mediators are not likely to directly contribute to ROS-mediated liver damage and (ii) mitoTEMPO is more likely to affect the redox status of liver cells reflected in a redox change of paramagnetic molecules. Further studies are necessary to understand these mechanisms. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

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16 pages, 2110 KiB

Open AccessArticle

Timing of Chromosome DNA Integration throughout the Yeast Cell Cycle

by Valentina Tosato, Beatrice Rossi, Jason Sims and Carlo V. Bruschi

Biomolecules 2023, 13(4), 614; https://doi.org/10.3390/biom13040614 - 29 Mar 2023

Viewed by 1276

Abstract

The dynamic mechanism of cell uptake and genomic integration of exogenous linear DNA still has to be completely clarified, especially within each phase of the cell cycle. We present a study of integration events of double-stranded linear DNA molecules harboring at their ends [...] Read more.

The dynamic mechanism of cell uptake and genomic integration of exogenous linear DNA still has to be completely clarified, especially within each phase of the cell cycle. We present a study of integration events of double-stranded linear DNA molecules harboring at their ends sequence homologies to the host’s genome, all throughout the cell cycle of the model organism Saccharomyces cerevisiae, comparing the efficiency of chromosomal integration of two types of DNA cassettes tailored for site-specific integration and bridge-induced translocation. Transformability increases in S phase regardless of the sequence homologies, while the efficiency of chromosomal integration during a specific cycle phase depends upon the genomic targets. Moreover, the frequency of a specific translocation between chromosomes XV and VIII strongly increased during DNA synthesis under the control of Pol32 polymerase. Finally, in the null POL32 double mutant, different pathways drove the integration in the various phases of the cell cycle and bridge-induced translocation was possible outside the S phase even without Pol32. The discovery of this cell-cycle dependent regulation of specific pathways of DNA integration, associated with an increase of ROS levels following translocation events, is a further demonstration of a sensing ability of the yeast cell in determining a cell-cycle-related choice of DNA repair pathways under stress. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

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13 pages, 2868 KiB

Open AccessArticle

Spontaneous Mutation Rates and Spectra of Respiratory-Deficient Yeast

by Xinyu Tu, Fan Wang, Gianni Liti, Michael Breitenbach, Jia-Xing Yue and Jing Li

Biomolecules 2023, 13(3), 501; https://doi.org/10.3390/biom13030501 - 09 Mar 2023

Cited by 1 | Viewed by 1946

Abstract

The yeast petite mutant was first discovered in the yeast Saccharomyces cerevisiae, which shows growth stress due to defects in genes encoding the respiratory chain. In a previous study, we described that deletion of the nuclear-encoded gene MRPL25 leads to mitochondrial genome [...] Read more.

The yeast petite mutant was first discovered in the yeast Saccharomyces cerevisiae, which shows growth stress due to defects in genes encoding the respiratory chain. In a previous study, we described that deletion of the nuclear-encoded gene MRPL25 leads to mitochondrial genome (mtDNA) loss and the petite phenotype, which can be rescued by acquiring ATP3 mutations. The mrpl25Δ strain showed an elevated SNV (single nucleotide variant) rate, suggesting genome instability occurred during the crisis of mtDNA loss. However, the genome-wide mutation landscape and mutational signatures of mitochondrial dysfunction are unknown. In this study we profiled the mutation spectra in yeast strains with the genotype combination of MRPL25 and ATP3 in their wildtype and mutated status, along with the wildtype and cytoplasmic petite rho0 strains as controls. In addition to the previously described elevated SNV rate, we found the INDEL (insertion/deletion) rate also increased in the mrpl25Δ strain, reinforcing the occurrence of genome instability. Notably, although both are petites, the mrpl25Δ and rho0 strains exhibited different INDEL rates and transition/transversion ratios, suggesting differences in the mutational signatures underlying these two types of petites. Interestingly, the petite-related mutagenesis effect disappeared when ATP3 suppressor mutations were acquired, suggesting a cost-effective mechanism for restoring both fitness and genome stability. Taken together, we present an unbiased genome-wide characterization of the mutation rates and spectra of yeast strains with respiratory deficiency, which provides valuable insights into the impact of respiratory deficiency on genome instability. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

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17 pages, 5436 KiB

Open AccessArticle

Quality Evaluation of Ophiopogon japonicus from Two Authentic Geographical Origins in China Based on Physicochemical and Pharmacological Properties of Their Polysaccharides

by Zherui Chen, Baojie Zhu, Xin Peng, Shaoping Li and Jing Zhao

Biomolecules 2022, 12(10), 1491; https://doi.org/10.3390/biom12101491 - 16 Oct 2022

Cited by 4 | Viewed by 1671

Abstract

Ophiopogon japonicus is widely used as a tonic herb in China. According to the origins, MaiDong of Chinese materia medica can be classified as Zhe MaiDong (Ophiopogon japonicus in Zhejiang), Chuan MaiDong (Ophiopogon japonicus in Sichuan), Duanting Shan MaiDong (Liriope [...] Read more.

Ophiopogon japonicus is widely used as a tonic herb in China. According to the origins, MaiDong of Chinese materia medica can be classified as Zhe MaiDong (Ophiopogon japonicus in Zhejiang), Chuan MaiDong (Ophiopogon japonicus in Sichuan), Duanting Shan MaiDong (Liriope muscari), and Hubei MaiDong (Liriope spicata). In terms of quality control, polysaccharides-based evaluations have not yet been conducted. In this study, microwave-assisted extraction (MAE) was used for the preparation of polysaccharides from 29 batches of MaiDong. HPSEC-MALLS-RID and HPAEC-PAD were employed to investigate their molecular parameters and compositional monosaccharides, respectively. The ability to scavenge ABTS radicals and immune promotion abilities, in terms of nitric oxide releasing and phagocytosis on RAW 264.7 macrophages, were also compared. The results showed that polysaccharides in different MaiDong varied in molecular parameters. All polysaccharides mainly contained fructose and glucose with small amounts of arabinose, mannose, galactose, and xylose. For polysaccharides of Zhe MaiDong and Chuan MaiDong, the molar ratio of Fru to Glc was roughly 15:1 and 14:1, respectively. Zhe MaiDong exhibited better antioxidant and immune promotion activity, and so did that of fibrous roots. The pharmacological activity, however, did not account for the variation in growth years. Finally, indicators for quality control based on multivariate statistical analysis included: yield, antioxidant activity, the content of fructose, and RI signal. It was concluded that MaiDong’s fibrous roots had similar components to the root, and their quality was not significantly affected by growth age. This may provide some guidance for the cultivation and use of MaiDong. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

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Review

Jump to: Research, Other

19 pages, 1370 KiB

Open AccessReview

Monogenic Disorders of ROS Production and the Primary Anti-Oxidative Defense

by Nana-Maria Grüning and Markus Ralser

Biomolecules 2024, 14(2), 206; https://doi.org/10.3390/biom14020206 - 09 Feb 2024

Viewed by 1081

Abstract

Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the cellular anti-oxidant defense mechanisms, plays a critical role in the pathogenesis of various human diseases. Redox metabolism, comprising a network of enzymes and genes, serves as a [...] Read more.

Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the cellular anti-oxidant defense mechanisms, plays a critical role in the pathogenesis of various human diseases. Redox metabolism, comprising a network of enzymes and genes, serves as a crucial regulator of ROS levels and maintains cellular homeostasis. This review provides an overview of the most important human genes encoding for proteins involved in ROS generation, ROS detoxification, and production of reduced nicotinamide adenine dinucleotide phosphate (NADPH), and the genetic disorders that lead to dysregulation of these vital processes. Insights gained from studies on inherited monogenic metabolic diseases provide valuable basic understanding of redox metabolism and signaling, and they also help to unravel the underlying pathomechanisms that contribute to prevalent chronic disorders like cardiovascular disease, neurodegeneration, and cancer. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

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18 pages, 316 KiB

Open AccessReview

“Molecular Biology”—Pleonasm or Denotation for a Discipline of Its Own? Reflections on the Origins of Molecular Biology and Its Situation Today

by Gregor P. Greslehner

Biomolecules 2023, 13(10), 1511; https://doi.org/10.3390/biom13101511 - 12 Oct 2023

Viewed by 938

Abstract

The disciplinary identity of molecular biology has frequently been called into question. Although the debates might sometimes have been more about creating or debunking myths, defending intellectual territory and the distribution of resources, there are interesting underlying questions about this area of biology [...] Read more.

The disciplinary identity of molecular biology has frequently been called into question. Although the debates might sometimes have been more about creating or debunking myths, defending intellectual territory and the distribution of resources, there are interesting underlying questions about this area of biology and how it is conceptually organized. By looking at the history of molecular biology, its origins and development, I examine the possible criteria for its status as a scientific discipline. Doing so allows us to answer the title question in such a way that offers a reasonable middle ground, where molecular biology can be properly viewed as a viable interdisciplinary program that can very well be called a discipline in its own right, even if no strict boundaries can be established. In addition to this historical analysis, a couple of systematic issues from a philosophy of science perspective allow for some assessment of the current situation and the future of molecular biology. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

12 pages, 1615 KiB

Open AccessReview

The History and Science of the Major Birch Pollen Allergen Bet v 1

by Heimo Breiteneder and Dietrich Kraft

Biomolecules 2023, 13(7), 1151; https://doi.org/10.3390/biom13071151 - 19 Jul 2023

Cited by 5 | Viewed by 1734

Abstract

The term allergy was coined in 1906 by the Austrian scientist and pediatrician Clemens Freiherr von Pirquet. In 1976, Dietrich Kraft became the head of the Allergy and Immunology Research Group at the Department of General and Experimental Pathology of the University of [...] Read more.

The term allergy was coined in 1906 by the Austrian scientist and pediatrician Clemens Freiherr von Pirquet. In 1976, Dietrich Kraft became the head of the Allergy and Immunology Research Group at the Department of General and Experimental Pathology of the University of Vienna. In 1983, Kraft proposed to replace natural extracts used in allergy diagnostic tests and vaccines with recombinant allergen molecules and persuaded Michael Breitenbach to contribute his expertise in molecular cloning as one of the mentors of this project. Thus, the foundation for the Vienna School of Molecular Allergology was laid. With the recruitment of Heimo Breiteneder as a young molecular biology researcher, the work began in earnest, resulting in the publication of the cloning of the first plant allergen Bet v 1 in 1989. Bet v 1 has become the subject of a very large number of basic scientific as well as clinical studies. Bet v 1 is also the founding member of the large Bet v 1-like superfamily of proteins with members—based on the ancient conserved Bet v 1 fold—being present in all three domains of life, i.e., archaea, bacteria and eukaryotes. This suggests that the Bet v 1 fold most likely already existed in the last universal common ancestor. The biological function of this protein was probably related to lipid binding. However, during evolution, a functional diversity within the Bet v 1-like superfamily was established. The superfamily comprises 25 families, one of which is the Bet v 1 family, which in turn is composed of 11 subfamilies. One of these, the PR-10-like subfamily of proteins, contains almost all of the Bet v 1 homologous allergens from pollen and plant foods. Structural and functional comparisons of Bet v 1 and its non-allergenic homologs of the superfamily will pave the way for a deeper understanding of the allergic sensitization process. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

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56 pages, 2374 KiB

Open AccessEditor’s ChoiceReview

The Janus-Faced Role of Lipid Droplets in Aging: Insights from the Cellular Perspective

by Nikolaus Bresgen, Melanie Kovacs, Angelika Lahnsteiner, Thomas Klaus Felder and Mark Rinnerthaler

Biomolecules 2023, 13(6), 912; https://doi.org/10.3390/biom13060912 - 30 May 2023

Cited by 3 | Viewed by 4011

Abstract

It is widely accepted that nine hallmarks—including mitochondrial dysfunction, epigenetic alterations, and loss of proteostasis—exist that describe the cellular aging process. Adding to this, a well-described cell organelle in the metabolic context, namely, lipid droplets, also accumulates with increasing age, which can be [...] Read more.

It is widely accepted that nine hallmarks—including mitochondrial dysfunction, epigenetic alterations, and loss of proteostasis—exist that describe the cellular aging process. Adding to this, a well-described cell organelle in the metabolic context, namely, lipid droplets, also accumulates with increasing age, which can be regarded as a further aging-associated process. Independently of their essential role as fat stores, lipid droplets are also able to control cell integrity by mitigating lipotoxic and proteotoxic insults. As we will show in this review, numerous longevity interventions (such as mTOR inhibition) also lead to strong accumulation of lipid droplets in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and mammalian cells, just to name a few examples. In mammals, due to the variety of different cell types and tissues, the role of lipid droplets during the aging process is much more complex. Using selected diseases associated with aging, such as Alzheimer’s disease, Parkinson’s disease, type II diabetes, and cardiovascular disease, we show that lipid droplets are “Janus”-faced. In an early phase of the disease, lipid droplets mitigate the toxicity of lipid peroxidation and protein aggregates, but in a later phase of the disease, a strong accumulation of lipid droplets can cause problems for cells and tissues. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

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Other

Jump to: Research, Review

10 pages, 289 KiB

Open AccessOpinion

Senopathies—Diseases Associated with Cellular Senescence

by Oleh Lushchak, Markus Schosserer and Johannes Grillari

Biomolecules 2023, 13(6), 966; https://doi.org/10.3390/biom13060966 - 08 Jun 2023

Cited by 2 | Viewed by 2022

Abstract

Cellular senescence describes a stable cell cycle arrest state with a characteristic phenotype. Senescent cells accumulate in the human body during normal aging, limiting the lifespan and promoting aging-related, but also several non-related, pathologies. We propose to refer to all diseases whose pathogenesis [...] Read more.

Cellular senescence describes a stable cell cycle arrest state with a characteristic phenotype. Senescent cells accumulate in the human body during normal aging, limiting the lifespan and promoting aging-related, but also several non-related, pathologies. We propose to refer to all diseases whose pathogenesis or progression is associated with cellular senescence as “senopathies”. Targeting senescent cells with senolytics or senomorphics is likely to mitigate these pathologies. Examples of senopathies include cardiovascular, metabolic, musculoskeletal, liver, kidney, and lung diseases and neurodegeneration. For all these pathologies, animal studies provide clear mechanistic evidence for a connection between senescent cell accumulation and disease progression. The major persisting challenge in developing novel senotherapies is the heterogeneity of senescence phenotypes, causing a lack of universal biomarkers and difficulties in discriminating senescent from non-senescent cells. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

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