Whole-transcriptome RNA sequencing reveals CeRNA regulatory network under long-term space composite stress in Rats.

To systematically evaluate the effect of simulated long-term spaceflight composite stress (LSCS) in hippocampus and gain more insights into the transcriptomic landscape and molecular mechanism, we performed whole-transcriptome sequencing based on the control group (Ctrl) and the simulated long-term spaceflight composite stress group (LSCS) from six hippocampus of rats. Subsequently, differential expression analysis was performed on the Ctrl and LSCS groups, followed by enrichment analysis and functional interaction prediction analysis to investigate gene-regulatory circuits in LSCS. In addition, competitive endogenous RNA (ceRNA) network was constructed to gain insights into genetic interaction. The result showed that 276 differentially expressed messenger RNAs (DEmRNAs), 139 differentially expressed long non-coding RNAs (DElncRNAs), 103 differentially expressed circular RNAs (DEcircRNAs), and 52 differentially expressed microRNAs (DEmiRNAs) were found in LSCS samples compared with the controls, which were then subjected to enrichment analysis of Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways to find potential functions. PI3K-Akt signaling pathway and MAPK signaling pathway may play fundamental roles in the pathogenesis of LSCS. A ceRNA network was constructed with the predicted 340 DE pairs, which revealed the interaction roles of 220 DEmiRNA-DEmRNA pairs, 76 DEmiRNA-DElncRNA pairs, and 44 DEmiRNA-DEcircRNA pairs. Further, Thrombospondins2 was found to be a key target among those ceRNAs. Overall, we conducted for the first time a full transcriptomic analysis of the response of hippocampus to the LSCS that involved a potential ceRNA network, thus providing a basis to study the underlying mechanism of the LSCS.

Muscle stem cell niche dynamics during muscle homeostasis and regeneration.

The process of skeletal muscle regeneration involves a coordinated interplay of specific cellular and molecular interactions within the injury site. This review provides an overview of the cellular and molecular components in regenerating skeletal muscle, focusing on how these cells or molecules in the niche regulate muscle stem cell functions. Dysfunctions of muscle stem cell-to-niche cell communications during aging and disease will also be discussed. A better understanding of how niche cells coordinate with muscle stem cells for muscle repair will greatly aid the development of therapeutic strategies for treating muscle-related disorders.

Permanent neonatal diabetes-causing insulin mutations have dominant negative effects on beta cell identity.

OBJECTIVE: Heterozygous coding sequence mutations of the INS gene are a cause of permanent neonatal diabetes (PNDM), requiring insulin therapy similar to T1D. While the negative effects on insulin processing and secretion are known, how dominant insulin mutations result in a continued decline of beta cell function after birth is not well understood. METHODS: We explored the causes of beta cell failure in two PNDM patients with two distinct INS mutations using patient-derived iPSCs and mutated hESCs. RESULTS: we detected accumulation of misfolded proinsulin and impaired proinsulin processing in vitro, and a dominant-negative effect of these mutations on beta-cell mass and function after transplantation into mice. In addition to anticipated ER stress, we found evidence of beta-cell dedifferentiation, characterized by an increase of cells expressing both Nkx6.1 and ALDH1A3, but negative for insulin and glucagon. CONCLUSIONS: These results highlight a novel mechanism, the loss of beta cell identity, contributing to the loss and functional failure of human beta cells with specific insulin gene mutations.

Protective effect of Baoyuan Jieyu formula on long-term spaceflight composite stress-induced depressive-like behavior and memory deficits through regulation of Ca2+ channel currents.

Long-term spaceflight composite stress (LSCS) can cause adverse effects on human systems, especially the central nervous system. This study aimed to identify the underlying mechanisms of the protective effect of Baoyuan Jieyu Formula (BYJYF) on LSCS-induced depressive-like behavior and memory deficits. In this experiment, we simulated the real space station environment for a period of 42 days. Novel object recognition test and forced swimming test were used to assess the memory abilities and depression level of rats as well as test the therapeutic effects of BYJYF treatment. Results showed LSCS could induce depressive-like behavior and damage short-term memory in the behavioral level, and BYJYF could enhance the ability to resist LSCS. Meanwhile, LSCS increased the levels of CRH, ACTH, and CORT and induced HPA axis hyperactivity, which can be relieved by BYJYF. Further, we predicted and verified the potential signaling pathways of BYJYF. Results showed BYJYF may reverse the inhibition of LSCS on Ca2+ channel currents. And we also found that BYJYF may exert its medicinal effects via four main active components including saikosaponin A. Overall, BYJYF exhibited protective effects against LSCS-induced depressive-like behavior and memory deficits, which might be ascribed to the regulation of Ca2+ channel currents and four active components. And it might become a promising candidate medicine for diseases induced by LSCS.

Long-term spaceflight composite stress induces depressive behaviors in model rats through disrupting hippocampus synaptic plasticity.

INTRODUCTION: Long-term spaceflight composite stress (LSCS) can cause adverse effects on human systems, including the central nervous system, which could trigger anxiety and depression. AIMS: This study aimed to identify changes in hippocampus synaptic plasticity under LSCS. METHODS: The present study simulated the real long-term space station environment by conducting a 42-day experiment that involved simulating microgravity, isolation, noise, circadian rhythm disruptions, and low pressure. The mood and behavior of the rats were assessed by behavior test. Transmission electron microscopy and patch-clamp were used to detect the changes in synapse morphology and electrophysiology, and finally, the expression of NMDA receptor channel proteins was detected by western blotting. RESULTS: The results showed that significant weight loss, anxiety, and depressive behaviors in rats were observed after being exposed to LSCS environment for 42 days. The synaptic structure was severely damaged, manifested as an obvious decrease in postsynaptic density thickness and synaptic interface curvature (p < 0.05; p < 0.05, respectively). Meanwhile, LTP was significantly impaired (p < 0.0001), and currents in the NMDAR channel were also significantly reduced (p < 0.0001). Further analysis found that LSCS decreased the expression of two key subtype proteins on this channel. CONCLUSION: These results suggested that LSCS-induced depressive behaviors by impairing synaptic plasticity in rat hippocampus.

Long-term spaceflight composite stress induces depression and cognitive impairment in astronauts-insights from neuroplasticity.

The environment on the space station is quite unique compared to Earth, which is a composite of multiple stressors, such as microgravity, isolation, confinement, noise, circadian rhythm disturbance, and so on. During prolonged space missions, astronauts have to stay in such extreme environments for long periods, which could induce adverse effects on both their physical and mental health. In some circumstances, this kind of long-term spaceflight composite stress (LSCS) could also induce depression and cognitive impairment in various ways, including dysregulating the neuroplasticity of the brains of astronauts, which should be attached to great importance. Here, we have comprehensively reviewed the impact of individual and combined stressors on depression and cognitive function during long-term spaceflight, explained the underlying mechanisms of those effects from the perspective of neuroplasticity, and current countermeasures for mitigating these challenges. This review provides insights into LSCS and potential neuroplasticity mechanisms, current with potentially great impact for understanding and mitigating the mental health risks and traumas of career astronauts and space tourists.

Permanent Neonatal diabetes-causing Insulin mutations have dominant negative effects on beta cell identity.

Heterozygous coding sequence mutations of the INS gene are a cause of permanent neonatal diabetes (PNDM) that results from beta cell failure. We explored the causes of beta cell failure in two PNDM patients with two distinct INS mutations. Using b and mutated hESCs, we detected accumulation of misfolded proinsulin and impaired proinsulin processing in vitro, and a dominant-negative effect of these mutations on the in vivo performance of patient-derived SC-beta cells after transplantation into NSG mice. These insulin mutations derange endoplasmic reticulum (ER) homeostasis, and result in the loss of beta-cell mass and function. In addition to anticipated apoptosis, we found evidence of beta-cell dedifferentiation, characterized by an increase of cells expressing both Nkx6.1 and ALDH1A3, but negative for insulin and glucagon. These results highlight both known and novel mechanisms contributing to the loss and functional failure of human beta cells with specific insulin gene mutations.

Effect of spaceflight on the phenotype and proteome of Escherichia coli.

Microbial safety has become a research hotspot with the development of manned space technology. Escherichia coli is a conditional pathogen that can cause infectious diseases. Therefore, it is necessary to study the influence of the space environment on E. coli. Phenotypic experiments including growth curves, morphology, and environmental resistance experiment were used to study the phenotypic changes of E. coli after exposure to the space environment for 12 days carried by the "SJ-10" satellite. Tandem mass tag was used to assess the proteome change of E. coli. We found that the survival rate of E. coli in the spaceflight group was decreased when cultivated in acidic and high-salt environments. Proteomic analysis identified 72 downregulated proteins involved in chemotaxis, intracellular pH elevation, glycolate catabolic process, and glutamate metabolic process in the spaceflight group. Meanwhile, only one protein mtr that was involved in the uptake of tryptophan in E. coli was upregulated in the spaceflight group. Our research showed that proteomics results can explain phenotypic results, which demonstrated the successful application of proteomics in mechanism research. Our data provide a comprehensive resource for understanding the effect of the space environment on E. coli.

Acanthopanax senticosus extract alleviates radiation-induced learning and memory impairment based on neurotransmitter-gut microbiota communication.

BACKGROUND: Acanthopanax senticosus (AS) is a medicinal and food plant with many physiological functions, especially nerve protection. Its extract has many functional components, including polysaccharides, flavonoids, saponins, and amino acids. Our previous study indicated that AS extract protected against nerve damage caused by radiation. However, little is known about the gut-brain axis mechanism of AS and its impact on radiation-induced learning and memory impairment. METHOD: In 60 Co-γ ray-irradiated mice, we investigated the changes in behavior, neurotransmitters and gut microbiota after different days of administration of AS extract as a dietary supplement. RESULTS: The AS extract improved learning and memory ability in mice, and the neurotransmitter levels in the hippocampus and colon started to change from the 7th day, which accompanied changes of the gut microbiota, a decreased abundance of Helicobacter on the 7th day and an increased abundance of Lactobacillus on the 28th day. Among the marker bacteria, Ruminococcus and Clostridiales were associated with 5-HT synthesis, and Streptococcus were associated with 5-HT and ACH synthesis. In addition, the AS extract increased the tight junction protein, inhibited inflammation levels in colon, and even increased the relative protein expression of BDNF and NF-κB and decreased the relative protein expression of IκBα in the hippocampus of irradiated mice. CONCLUSION: These results will lay the foundation for further study on the mechanism of the gut-brain axis of AS in preventing radiation-induced learning and memory impairment.

Combining Proteomics and Metabolomics to Analyze the Effects of Spaceflight on Rice Progeny.

Spaceflight is a special abiotic stress, the biological effect mechanism of which on contemporary rice has been clarified, However, its effect on offspring rice was still unclear. In order to understand the response mechanism of F2 generation plants to space flight, this study used SJ-10 recoverable satellite to carry DN423 rice seeds for 12.5 days in orbit flight. After returning to the ground, the plants were then planted to F2 generation to explore the biological effect mechanism. Our research showed that in the F2 generation of TLS, the rice plant height of the space flight group increased by 33.8%, the ear length and thousand-grain weight decreased by 9.7 and 4.6%, respectively, and the grain number per panicle increased by 6.5%. Moreover, related proteins that control changes in agronomic traits have been identified. The changes of MDA, H2O2, soluble sugar, electron leakage and antioxidant enzyme activity confirmed the stress response in F2 generation plants. ITRAQ and LC-MS technology were used to reveal the change pattern of protein levels and metabolite levels in F2 generation plants, 389 and 405 proteins were identified as differentially abundant proteins in TLS and TS, respectively. In addition, there were 124 and 125 metabolites that changed during these two periods. The proteome and metabolome result further confirmed that the F2 generation plants still retained the memory of space flight stress, and retained the memory of space flight stress through genome instability. Oxidative stress signals activated sugar signals to rebuild metabolic networks to adapt to space flight stress. The reconstruction of energy metabolism, amino acid metabolism, phenylalanine metabolism, and flavonoid metabolism played an important role in the process of adapting to space flight stress. The results of this study broaden the perspective of space biological effects and provide a basis for studying the effects of abiotic stress on plant progeny.

The Memory of Rice Response to Spaceflight Stress: From the Perspective of Metabolomics and Proteomics.

The stress response of plants to spaceflight has been confirmed in contemporary plants, and plants retained the memory of spaceflight through methylation reaction. However, how the progeny plants adapt to this cross-generational stress memory was rarely reported. Here, we used the ShiJian-10 retractable satellite carrying Dongnong416 rice seeds for a 12.5-day on-orbit flight and planted the F2 generation after returning to the ground. We evaluated the agronomic traits of the F2 generation plants and found that the F2 generation plants had no significant differences in plant height and number of tillers. Next, the redox state in F2 plants was evaluated, and it was found that the spaceflight broke the redox state of the F2 generation rice. In order to further illustrate the stress response caused by this redox state imbalance, we conducted proteomics and metabolomics analysis. Proteomics results showed that the redox process in F2 rice interacts with signal transduction, stress response, and other pathways, causing genome instability in the plant, leading to transcription, post-transcriptional modification, protein synthesis, protein modification, and degradation processes were suppressed. The metabolomics results showed that the metabolism of the F2 generation plants was reshaped. These metabolic pathways mainly included amino acid metabolism, sugar metabolism, cofactor and vitamin metabolism, purine metabolism, phenylpropane biosynthesis, and flavonoid metabolism. These metabolic pathways constituted a new metabolic network. This study confirmed that spaceflight affected the metabolic changes in offspring rice, which would help better understand the adaptation mechanism of plants to the space environment.

Baoyuan jieyu formula ameliorates depression-like behaviour in rats induced by simulated long-term spaceflight composite stress through regulating MAPK and BDNF pathways.

During space flight, astronauts are exposed to various influences of extreme environments and susceptible to develop depression-like behavior. Thus, this study aims to explore the molecular biological mechanism of the cause of depression-like behavior and reveal the effect of Baoyuan Jieyu Formula (BYJYF) on ameliorating depression-like behavior. Here, rats exposed to simulated long-term spaceflight composite stress (LSCS) reduced the sucrose preference rate (P <0.01), and the time of forced swimming immobility and the number of climbing times were also reduced (P < 0.01, P < 0.001). Moreover, the number of neurons in the CA3 region of the hippocampus decreased ( P< 0.01, P < 0.05, P < 0.001), the staining became weak, and the Nissl body decreased. Antibody chip detected a total of 854 protein molecules in the hippocampus, of which 51 and 37 proteins were significantly different in the LSCS group and LSCS+BYJYF group, respectively, focusing on signaling pathways such as MAPK and neurotrophin. Western blot was used to verify the related proteins of these two pathways. Conclusively, simulated LSCS can induce depression-like behavior and neuronal damage. BYJYF can reduce neuronal apoptosis, and promote neuron survival by regulating the MAPK and the neurotrophin signaling pathway to protect neurons and combat LSCS.

Metabolomics Analysis in Different Development Stages on SP0 Generation of Rice Seeds After Spaceflight.

Spaceflight is a special abiotic stress condition. In recent years, it has been confirmed that the spaceflight caused the stress response of rice seeds, and the protein level, transcription level, and methylation level will change during the planting process after returning to the ground. However, the changes at the metabolome level are not very clear. In this study, two kinds of rice seeds, Dongnong423 (DN3) and Dongnong416 (DN6), were carried on the ShiJian-10 retractable satellite (SJ-10) for 12.5 days in orbit, returned to the ground and planted in the field until the three-leaf (TLP) and tillering stage (TS). The results of antioxidant enzyme activity, soluble sugar, and electron leakage rate revealed that the spaceflight caused the stress response of rice. The TLP and TS of DN3 identified 110 and 57 different metabolites, respectively, while the TLP and TS of DN6 identified 104 and 74 different metabolites, respectively. These metabolites included amino acids, sugars, fatty acids, organic acids and secondary metabolites. We used qRT-PCR technology to explore the changes of enzyme genes in the tricarboxylic acid cycle (TCA) and amino acid metabolism pathway. Combined with the results of metabolomics, we determined that during the TLP, the TCA cycle rate of DN3 was inhibited and amino acid metabolism was activated, while the TCA cycle rate of DN6 was activated and amino acid metabolism was inhibited. In TS, the TCA cycle rate of DN3 was inhibited, and amino acid metabolism was not significantly changed, while the TCA cycle rate of DN6 was activated and amino acid metabolism was inhibited. These results suggested that the response mechanisms of the two different rice strains to spaceflight stress are different, and these differences may be reflected in energy consumption and compound biosynthesis of rice in different growth and development stages. This study provided new insights for further exploring the effects of spaceflight.

Proteomic analysis in different development stages on SP0 generation of rice seeds after space flight.

The space biological effects of plants will drive the development of aerospace science and breeding science. The aim of this study is to reveal changes in the proteome of contemporary plants at different growth and development stages after space flight of rice seeds. We carried the rice seeds (DN416) through the SJ-10 returning satellite and returned to the ground for planting to the three-leaf stage (TLP) and tillering stage (TS) after a 12.5-day orbital flight. We found that the space flight caused the rice germination rate, the TLP plant height, and the number of tillers in the TS decreased by 11.64%, 9.75%, and 9.80%, respectively. In addition, the treatment group ROS and MDA level increased in the TLP and TS. The abundance patterns of proteins in these leaves identified 214 proteins in the TLP and 286 in the TS leaves that were markedly changed. Moreover, our study identified D14 proteins that control plant height and tiller. Our results show that the space environment may affect the downstream signaling mechanism by regulating the level of ROS in the body to achieve a response to the space environment. Meanwhile, the space environment may affect the plant height and tiller of rice by altering the expression of D14 protein and hormone-regulated proteins. Our results reveal changes in the proteome of different growth stages of rice plants, and also reveal the molecular mechanism of space environment regulation of rice plant height and tiller, which provides a new direction for further understanding of space biological effects and space mutation breeding.

Oxidovanadium(V) and Dioxidomolybdenum(VI) Complexes of N'-(3,5-Dichloro-2-hydroxybenzylidene)-4-fluorobenzohydrazide: Synthesis, Characterization, Crystal Structures and Catalytic Property.

N'-(3,5-Dichloro-2-hydroxybenzylidene)-4-fluorobenzohydrazide (H2L) was used to prepare oxidovanadium(V) complex [VOL(OEt)(MeOH)] (1) and dioxidomolybdenum(VI) complex [MoO2L(OH2)]·[MoO2L(EtOH)] (2). The complexes were characterized by IR, UV-Vis, NMR spectroscopy, and single crystal X-ray diffraction. X-ray analysis indicates that the complexes are mononuclear species with the metal atoms in octahedral coordination. The complexes were studied for catalytic oxidation property on some olefins with tert-butyl hydroperoxide as oxidant.

Simulated spatial radiation impacts learning and memory ability with alterations of neuromorphology and gut microbiota in mice.

Complex space environments, including microgravity and radiation, affect the body's central nervous system, endocrine system, circulatory system, and reproductive system. Radiation-induced aberration in the neuronal integrity and cognitive functions are particularly well known. Moreover, ionizing radiation is a likely contributor to alterations in the microbiome. However, there is a lacuna between radiation-induced memory impairment and gut microbiota. The present study was aimed at investigating the effects of simulated space-type radiation on learning and memory ability and gut microbiota in mice. Adult mice were irradiated by 60Co-γ rays at 4 Gy to simulate spatial radiation; behavioral experiments, pathological experiments, and transmission electron microscopy all showed that radiation impaired learning and memory ability and hippocampal neurons in mice, which was similar to the cognitive impairment in neurodegenerative diseases. In addition, we observed that radiation destroyed the colonic structure of mice, decreased the expression of tight junction proteins, and increased inflammation levels, which might lead to dysregulation of the intestinal microbiota. We found a correlation between the brain and colon in the changes in neurotransmitters associated with learning and memory. The 16S rRNA results showed that the bacteria associated with these neurotransmitters were also changed at the genus level and were significantly correlated. These results indicate that radiation-induced memory and cognitive impairment can be linked to gut microbiota through neurotransmitters.