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Cellular and Molecular Signaling Meet the Space Environment 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 30521

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Prof. Dr. John Lawler

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Department of Health and Kinesiology, Graduate Faculty of Nutrition, Texas A&M University, College Station, TX, USA
Interests: nitric oxide; free radicals; skeletal muscle function; oxidative stress
Special Issues, Collections and Topics in MDPI journals

Dr. Khaled Kamal

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Department of Health and Kinesiology, Graduate Faculty of Nutrition, Texas A&M University, College Station, TX, USA
Interests: microgravity environments; cell biology; oxidative stress; skeletal muscle
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue, “Cellular and Molecular Signaling Meet the Space Environment”.

The future of spaceflight missions to the Moon and extended human presence on the Martian surface necessitates seeking answers to the mysteries of organismal adaptation during spaceflight when exposed to microgravity and radiation. In particular, the cellular and molecular adaptations to the microgravitational environments of space travel are critical areas of microgravitational research. Gravity has been a constant stressor throughout evolutionary history on Earth. Therefore, it would be expected that sudden changes in gravitational forces directly catalyze alterations and adaptations in normal biological morphology and function. An important focus of this research topic is:

What are the underlying mechanisms by which a wide range of living organisms can adapt themselves to the space environment without the normal, essential cues for their existence and survival on our planet Earth?
What happens to microorganisms, plants, and zoological life at the cellular level?
What mechanisms are essential to the health, well-being, and performance of astronauts during spaceflight and the gravitational alterations?
What type of molecular mechanisms are important: DNA damage, cell cycle regulation, mechanotransduction, cell signaling protein expression, and post-translational alterations?
Is the genome responding in a concerted way by means of epigenetics, chromatin re-organization or via other genome stabilization mechanisms?

Prof. Dr. John Lawler
Dr. Khaled Kamal
Guest Editors

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Keywords

space exploration
microgravity
space radiation
cellular mechanism
astronaut health

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Related Special Issue

Cellular and Molecular Signaling Meet the Space Environment (3rd Edition) in International Journal of Molecular Sciences (4 articles)

Published Papers (10 papers)

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Research

Jump to: Review

14 pages, 4040 KiB

Open AccessArticle

Smooth Muscle Actin as a Criterion for Gravisensitivity of Stomach and Jejunum in Laboratory Rodents

by Tatyana Samoilenko, Viktoriya Shishkina, Lyubov Antakova, Yelena Goryushkina, Andrey Kostin, Igor Buchwalow, Markus Tiemann and Dmitrii Atiakshin

Int. J. Mol. Sci. 2023, 24(22), 16539; https://doi.org/10.3390/ijms242216539 - 20 Nov 2023

Cited by 1 | Viewed by 2838

Abstract

Smooth muscle tissue (SMT) is one of the main structural components of visceral organs, acting as a key factor in the development of adaptive and pathological conditions. Despite the crucial part of SMT in the gastrointestinal tract activity, the mechanisms of its gravisensitivity are still insufficiently studied. The study evaluated the content of smooth muscle actin (α-SMA) in the membranes of the gastric fundus and jejunum in C57BL/6N mice (30-day space flight), in Mongolian gerbils Meriones unguiculatus (12-day orbital flight) and after anti-orthostatic suspension according to E.R. Morey-Holton. A morphometric analysis of α-SMA in the muscularis externa of the stomach and jejunum of mice and Mongolian gerbils from space flight groups revealed a decreased area of the immunopositive regions, a fact indicating a weakening of the SMT functional activity. Gravisensitivity of the contractile structures of the digestive system may be due to changes in the myofilament structural components of the smooth myocytes or myofibroblast actin. A simulated antiorthostatic suspension revealed no significant changes in the content of the α-SMA expression level, a fact supporting an alteration in the functional properties of the muscularis externa of the digestive hollow organs under weightless environment. The data obtained contribute to the novel mechanisms of the SMT contractile apparatus remodeling during orbital flights and can be used to improve preventive measures in space biomedicine. Full article

(This article belongs to the Special Issue Cellular and Molecular Signaling Meet the Space Environment 2.0)

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14 pages, 2214 KiB

Open AccessArticle

Modelled-Microgravity Reduces Virulence Factor Production in Staphylococcus aureus through Downregulation of agr-Dependent Quorum Sensing

by Macauley J. Green, Ewan J. Murray, Paul Williams, Amir M. Ghaemmaghami, Jonathan W. Aylott and Philip M. Williams

Int. J. Mol. Sci. 2023, 24(21), 15997; https://doi.org/10.3390/ijms242115997 - 6 Nov 2023

Cited by 5 | Viewed by 2247

Abstract

Bacterial contamination during space missions is problematic for human health and damages filters and other vital support systems. Staphylococcus aureus is both a human commensal and an opportunistic pathogen that colonizes human tissues and causes acute and chronic infections. Virulence and colonization factors are positively and negatively regulated, respectively, by bacterial cell-to-cell communication (quorum sensing) via the agr (accessory gene regulator) system. When cultured under low-shear modelled microgravity conditions (LSMMG), S. aureus has been reported to maintain a colonization rather than a pathogenic phenotype. Here, we show that the modulation of agr expression via reduced production of autoinducing peptide (AIP) signal molecules was responsible for this behavior. In an LSMMG environment, the S. aureus strains JE2 (methicillin-resistant) and SH1000 (methicillin-sensitive) both exhibited reduced cytotoxicity towards the human leukemia monocytic cell line (THP-1) and increased fibronectin binding. Using S. aureus agrP3::lux reporter gene fusions and mass spectrometry to quantify the AIP concentrations, the activation of agr, which depends on the binding of AIP to the transcriptional regulator AgrC, was delayed in the strains with an intact autoinducible agr system. This was because AIP production was reduced under these growth conditions compared with the ground controls. Under LSMMG, S. aureus agrP3::lux reporter strains that cannot produce endogenous AIPs still responded to exogenous AIPs. Provision of exogenous AIPs to S. aureus USA300 during microgravity culture restored the cytotoxicity of culture supernatants for the THP-1 cells. These data suggest that microgravity does not affect AgrC-AIP interactions but more likely the generation of AIPs. Full article

(This article belongs to the Special Issue Cellular and Molecular Signaling Meet the Space Environment 2.0)

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18 pages, 3610 KiB

Open AccessArticle

Functional Meta-Analysis of the Proteomic Responses of Arabidopsis Seedlings to the Spaceflight Environment Reveals Multi-Dimensional Sources of Variability across Spaceflight Experiments

by Gbolaga O. Olanrewaju, Colin P. S. Kruse and Sarah E. Wyatt

Int. J. Mol. Sci. 2023, 24(19), 14425; https://doi.org/10.3390/ijms241914425 - 22 Sep 2023

Cited by 5 | Viewed by 2396

Abstract

The human quest for sustainable habitation of extraterrestrial environments necessitates a robust understanding of life’s adaptability to the unique conditions of spaceflight. This study provides a comprehensive proteomic dissection of the Arabidopsis plant’s responses to the spaceflight environment through a meta-analysis of proteomics data from four separate spaceflight experiments conducted on the International Space Station (ISS) in different hardware configurations. Raw proteomics LC/MS spectra were analyzed for differential expression in MaxQuant and Perseus software. The analysis of dissimilarities among the datasets reveals the multidimensional nature of plant proteomic responses to spaceflight, impacted by variables such as spaceflight hardware, seedling age, lighting conditions, and proteomic quantification techniques. By contrasting datasets that varied in light exposure, we elucidated proteins involved in photomorphogenesis and skotomorphogenesis in plant spaceflight responses. Additionally, with data from an onboard 1 g control experiment, we isolated proteins that specifically respond to the microgravity environment and those that respond to other spaceflight conditions. This study identified proteins and associated metabolic pathways that are consistently impacted across the datasets. Notably, these shared proteins were associated with critical metabolic functions, including carbon metabolism, glycolysis, gluconeogenesis, and amino acid biosynthesis, underscoring their potential significance in Arabidopsis’ spaceflight adaptation mechanisms and informing strategies for successful space farming. Full article

(This article belongs to the Special Issue Cellular and Molecular Signaling Meet the Space Environment 2.0)

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15 pages, 10720 KiB

Open AccessArticle

Space-Flight- and Microgravity-Dependent Alteration of Mast Cell Population and Protease Expression in Digestive Organs of Mongolian Gerbils

by Dmitrii Atiakshin, Andrey Kostin, Viktoriya Shishkina, Alexandra Burtseva, Anastasia Buravleva, Artem Volodkin, Daniel Elieh-Ali-Komi, Igor Buchwalow and Markus Tiemann

Int. J. Mol. Sci. 2023, 24(17), 13604; https://doi.org/10.3390/ijms241713604 - 2 Sep 2023

Cited by 7 | Viewed by 1863

Abstract

Mast cell (MC)-specific proteases are of particular interest for space biology and medicine due to their biological activity in regulating targets of a specific tissue microenvironment. MC tryptase and chymase obtain the ability to remodel connective tissue through direct and indirect mechanisms. Yet, MC-specific protease expression under space flight conditions has not been adequately investigated. Using immunohistochemical stainings, we analyzed in this study the protease profile of the jejunal, gastric, and hepatic MC populations in three groups of Mongolian gerbils—vivarium control, synchronous experiment, and 12-day orbital flight on the Foton-M3 spacecraft—and in two groups—vivarium control and anti-orthostatic suspension—included in the experiment simulating effects of weightlessness in the ground-based conditions. After a space flight, there was a decreased number of MCs in the studied organs combined with an increased proportion of chymase-positive MCs and MCs with a simultaneous content of tryptase and chymase; the secretion of specific proteases into the extracellular matrix increased. These changes in the expression of proteases were observed both in the mucosal and connective tissue MC subpopulations of the stomach and jejunum. Notably, the relative content of tryptase-positive MCs in the studied organs of the digestive system decreased. Space flight conditions simulated in the synchronous experiment caused no similar significant changes in the protease profile of MC populations. The space flight conditions resulted in an increased chymase expression combined with a decreased total number of protease-positive MCs, apparently due to participating in the processes of extracellular matrix remodeling and regulating the state of the cardiovascular system. Full article

(This article belongs to the Special Issue Cellular and Molecular Signaling Meet the Space Environment 2.0)

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16 pages, 7155 KiB

Open AccessArticle

Spaceflight-Induced Gene Expression Profiles in the Mouse Brain Are Attenuated by Treatment with the Antioxidant BuOE

by Isaac Kremsky, Samir Ali, Seta Stanbouly, Jacob Holley, Stephen Justinen, Michael Pecaut, James Crapo and Xiaowen Mao

Int. J. Mol. Sci. 2023, 24(17), 13569; https://doi.org/10.3390/ijms241713569 - 1 Sep 2023

Cited by 2 | Viewed by 2708

Abstract

The demands of deep space pose a health risk to the central nervous system that has long been a concern when sending humans to space. While little is known about how spaceflight affects transcription spatially in the brain, a greater understanding of this process has the potential to aid strategies that mitigate the effects of spaceflight on the brain. Therefore, we performed GeoMx Digital Spatial Profiling of mouse brains subjected to either spaceflight or grounded controls. Four brain regions were selected: Cortex, Frontal Cortex, Corunu Ammonis I, and Dentate Gyrus. Antioxidants have emerged as a potential means of attenuating the effects of spaceflight, so we treated a subset of the mice with a superoxide dismutase mimic, MnTnBuOE-2-PyP 5+ (BuOE). Our analysis revealed hundreds of differentially expressed genes due to spaceflight in each of the four brain regions. Both common and region-specific transcriptomic responses were observed. Metabolic pathways and pathways sensitive to oxidative stress were enriched in the four brain regions due to spaceflight. These findings enhance our understanding of brain regional variation in susceptibility to spaceflight conditions. BuOE reduced the transcriptomic effects of spaceflight at a large number of genes, suggesting that this compound may attenuate oxidative stress-induced brain damage caused by the spaceflight environment. Full article

(This article belongs to the Special Issue Cellular and Molecular Signaling Meet the Space Environment 2.0)

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15 pages, 3151 KiB

Open AccessArticle

Comparative Analysis of Muscle Atrophy During Spaceflight, Nutritional Deficiency and Disuse in the Nematode Caenorhabditis elegans

by Ban-seok Kim, Alfredo V. Alcantara, Jr., Je-Hyun Moon, Atsushi Higashitani, Nahoko Higashitani, Timothy Etheridge, Nathaniel J. Szewczyk, Colleen S. Deane, Christopher J. Gaffney, Akira Higashibata, Toko Hashizume, Kyoung-hye Yoon and Jin I. Lee

Int. J. Mol. Sci. 2023, 24(16), 12640; https://doi.org/10.3390/ijms241612640 - 10 Aug 2023

Cited by 5 | Viewed by 4388

Abstract

While spaceflight is becoming more common than before, the hazards spaceflight and space microgravity pose to the human body remain relatively unexplored. Astronauts experience muscle atrophy after spaceflight, but the exact reasons for this and solutions are unknown. Here, we take advantage of the nematode C. elegans to understand the effects of space microgravity on worm body wall muscle. We found that space microgravity induces muscle atrophy in C. elegans from two independent spaceflight missions. As a comparison to spaceflight-induced muscle atrophy, we assessed the effects of acute nutritional deprivation and muscle disuse on C. elegans muscle cells. We found that these two factors also induce muscle atrophy in the nematode. Finally, we identified clp-4, which encodes a calpain protease that promotes muscle atrophy. Mutants of clp-4 suppress starvation-induced muscle atrophy. Such comparative analyses of different factors causing muscle atrophy in C. elegans could provide a way to identify novel genetic factors regulating space microgravity-induced muscle atrophy. Full article

(This article belongs to the Special Issue Cellular and Molecular Signaling Meet the Space Environment 2.0)

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16 pages, 2689 KiB

Open AccessArticle

The Impact of SRT2104 on Skeletal Muscle Mitochondrial Function, Redox Biology, and Loss of Muscle Mass in Hindlimb Unloaded Rats

by Lauren T. Wesolowski, Jessica L. Simons, Pier L. Semanchik, Mariam A. Othman, Joo-Hyun Kim, John M. Lawler, Khaled Y. Kamal and Sarah H. White-Springer

Int. J. Mol. Sci. 2023, 24(13), 11135; https://doi.org/10.3390/ijms241311135 - 6 Jul 2023

Cited by 6 | Viewed by 3836

Abstract

Mechanical unloading during microgravity causes skeletal muscle atrophy and impairs mitochondrial energetics. The elevated production of reactive oxygen species (ROS) by mitochondria and Nox2, coupled with impairment of stress protection (e.g., SIRT1, antioxidant enzymes), contribute to atrophy. We tested the hypothesis that the SIRT1 activator, SRT2104 would rescue unloading-induced mitochondrial dysfunction. Mitochondrial function in rat gastrocnemius and soleus muscles were evaluated under three conditions (10 days): ambulatory control (CON), hindlimb unloaded (HU), and hindlimb-unloaded-treated with SRT2104 (SIRT). Oxidative phosphorylation, electron transfer capacities, H₂O₂ production, and oxidative and antioxidant enzymes were quantified using high-resolution respirometry and colorimetry. In the gastrocnemius, (1) integrative (per mg tissue) proton LEAK was lesser in SIRT than in HU or CON; (2) intrinsic (relative to citrate synthase) maximal noncoupled electron transfer capacity (E_CI+II) was lesser, while complex I-supported oxidative phosphorylation to E_CI+II was greater in HU than CON; (3) the contribution of LEAK to E_CI+II was greatest, but cytochrome c oxidase activity was lowest in HU. In both muscles, H₂O₂ production and concentration was greatest in SIRT, as was gastrocnemius superoxide dismutase activity. In the soleus, H₂O₂ concentration was greater in HU compared to CON. These results indicate that SRT2104 preserves mitochondrial function in unloaded skeletal muscle, suggesting its potential to support healthy muscle cells in microgravity by promoting necessary energy production in mitochondria. Full article

(This article belongs to the Special Issue Cellular and Molecular Signaling Meet the Space Environment 2.0)

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12 pages, 1330 KiB

Open AccessArticle

The State of the Organs of the Female Reproductive System after a 5-Day “Dry” Immersion

by Elena Yu. Gorbacheva, Konstantin A. Toniyan, Yulia A. Biriukova, Nadezhda A. Lukicheva, Oleg I. Orlov, Valery V. Boyarintsev and Irina V. Ogneva

Int. J. Mol. Sci. 2023, 24(4), 4160; https://doi.org/10.3390/ijms24044160 - 19 Feb 2023

Cited by 7 | Viewed by 2056

Abstract

The impact of weightlessness on the female reproductive system remains poorly understood, although deep space exploration is impossible without the development of effective measures to protect women’s health. The purpose of this work was to study the effect of a 5-day “dry” immersion on the state of the reproductive system of female subjects. On the fourth day of the menstrual cycle after immersion, we observed an increase in inhibin B of 35% (p < 0.05) and a decrease in luteinizing hormone of 12% (p < 0.05) and progesterone of 52% (p < 0.05) compared with the same day before immersion. The size of the uterus and the thickness of the endometrium did not change. On the ninth day of the menstrual cycle after immersion, the average diameters of the antral follicles and the dominant follicle were, respectively, 14% and 22% (p < 0.05) higher than before. The duration of the menstrual cycle did not change. The obtained results may indicate that the stay in the 5-day “dry” immersion, on the one hand, can stimulate the growth of the dominant follicle, but, on the other hand, can cause functional insufficiency of the corpus lutea. Full article

(This article belongs to the Special Issue Cellular and Molecular Signaling Meet the Space Environment 2.0)

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21 pages, 3029 KiB

Open AccessArticle

Low-Speed Clinorotation of Brachypodium distachyon and Arabidopsis thaliana Seedlings Triggers Root Tip Curvatures That Are Reminiscent of Gravitropism

by Shih-Heng Su, Alexander Moen, Rien M. Groskopf, Katherine L. Baldwin, Brian Vesperman and Patrick H. Masson

Int. J. Mol. Sci. 2023, 24(2), 1540; https://doi.org/10.3390/ijms24021540 - 12 Jan 2023

Viewed by 2092

Abstract

Clinostats are instruments that continuously rotate biological specimens along an axis, thereby averaging their orientation relative to gravity over time. Our previous experiments indicated that low-speed clinorotation may itself trigger directional root tip curvature. In this project, we have investigated the root curvature response to low-speed clinorotation using Arabidopsis thaliana and Brachypodium distachyon seedlings as models. We show that low-speed clinorotation triggers root tip curvature in which direction is dictated by gravitropism during the first half-turn of clinorotation. We also show that the angle of root tip curvature is modulated by the speed of clinorotation. Arabidopsis mutations affecting gravity susception (pgm) or gravity signal transduction (arg1, toc132) are shown to affect the root tip curvature response to low-speed clinorotation. Furthermore, low-speed vertical clinorotation triggers relocalization of the PIN3 auxin efflux facilitator to the lateral membrane of Arabidopsis root cap statocytes, and creates a lateral gradient of auxin across the root tip. Together, these observations support a role for gravitropism in modulating root curvature responses to clinorotation. Interestingly, distinct Brachypodium distachyon accessions display different abilities to develop root tip curvature responses to low-speed vertical clinorotation, suggesting the possibility of using genome-wide association studies to further investigate this process. Full article

(This article belongs to the Special Issue Cellular and Molecular Signaling Meet the Space Environment 2.0)

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Review

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24 pages, 1538 KiB

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Drug Discovery Targeting Post-Translational Modifications in Response to DNA Damages Induced by Space Radiation

by Dafei Xie, Qi Huang and Pingkun Zhou

Int. J. Mol. Sci. 2023, 24(8), 7656; https://doi.org/10.3390/ijms24087656 - 21 Apr 2023

Cited by 3 | Viewed by 4635

Abstract

DNA damage in astronauts induced by cosmic radiation poses a major barrier to human space exploration. Cellular responses and repair of the most lethal DNA double-strand breaks (DSBs) are crucial for genomic integrity and cell survival. Post-translational modifications (PTMs), including phosphorylation, ubiquitylation, and SUMOylation, are among the regulatory factors modulating a delicate balance and choice between predominant DSB repair pathways, such as non-homologous end joining (NHEJ) and homologous recombination (HR). In this review, we focused on the engagement of proteins in the DNA damage response (DDR) modulated by phosphorylation and ubiquitylation, including ATM, DNA-PKcs, CtIP, MDM2, and ubiquitin ligases. The involvement and function of acetylation, methylation, PARylation, and their essential proteins were also investigated, providing a repository of candidate targets for DDR regulators. However, there is a lack of radioprotectors in spite of their consideration in the discovery of radiosensitizers. We proposed new perspectives for the research and development of future agents against space radiation by the systematic integration and utilization of evolutionary strategies, including multi-omics analyses, rational computing methods, drug repositioning, and combinations of drugs and targets, which may facilitate the use of radioprotectors in practical applications in human space exploration to combat fatal radiation hazards. Full article

(This article belongs to the Special Issue Cellular and Molecular Signaling Meet the Space Environment 2.0)

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