11 research outputs found

    Transcriptome sequencing of the naked mole rat (Heterocephalus glaber) and identification of hypoxia tolerance genes

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    The naked mole rat (NMR; Heterocephalus glaber) is a small rodent species found in regions of Kenya, Ethiopia and Somalia. It has a high tolerance for hypoxia and is thus considered one of the most important natural models for studying hypoxia tolerance mechanisms. The various mechanisms underlying the NMR's hypoxia tolerance are beginning to be understood at different levels of organization, and next-generation sequencing methods promise to expand this understanding to the level of gene expression. In this study, we examined the sequence and transcript abundance data of the muscle transcriptome of NMRs exposed to hypoxia using the Illumina HiSeq 2500 system to clarify the possible genomic adaptive responses to the hypoxic underground surroundings. The RNA-seq raw FastQ data were mapped against the NMR genome. We identified 2337 differentially expressed genes (DEGs) by comparison of the hypoxic and control groups. Functional annotation of the DEGs by gene ontology (GO) analysis revealed enrichment of hypoxia stress-related GO categories, including ‘biological regulation’, ‘cellular process’, ‘ion transport’ and ‘cell-cell signaling’. Enrichment of DEGs in signaling pathways was analyzed against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database to identify possible interactions between DEGs. The results revealed significant enrichment of DEGs in focal adhesion, the mitogen-activated protein kinase (MAPK) signaling pathway and the glycine, serine and threonine metabolism pathway. Furthermore, inhibition of DEGs (STMN1, MAPK8IP1 and MAPK10) expression induced apoptosis and arrested cell growth in NMR fibroblasts following hypoxia. Thus, this global transcriptome analysis of NMRs can provide an important genetic resource for the study of hypoxia tolerance in mammals. Furthermore, the identified DEGs may provide important molecular targets for biomedical research into therapeutic strategies for stroke and cardiovascular diseases

    Functional annotation of extensively and divergently expressed miRNAs in suprachiasmatic nucleus of Clock(Delta 19) mutant mice

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    Circadian locomotor output cycles kaput protein (CLOCK) is a core transcription factor of complex integrated feedback loops in mammalian circadian clock. More genes have been reported to be regulated by CLOCK, however little is known about the role of CLOCK-mediated miRNAs. To dissect this, we used microarray analysis to measure miRNAs expression in suprachiasmatic nuclei (SCN) of wild-type (WT) and Clock(Delta 19) mutant mice at two different time points. We found that miRNAs regulation in two time points was extensive (nearly 75% of the miRNAs expressed at each time point), and very little overlap, with only six miRNAs in common. Besides this, the predicted CLOCK regulated miRNAs at two time points participated in extremely diverse pathways. We validated nine miRNAs (miR-125a-3p, miR-144, miR-199a-5p, miR-199b*, miR-200a, miR-200b, miR-203, miR-449a, and miR-96), which were involved in the same signaling pathway-hippo signaling pathway. The rhythms of these miRNAs showed a broad distribution of phase, amplitude, and waveform in Clock mutation. And further analysis indicated that there may be three models of miRNA-mediated circadian rhythms and hippo signaling pathway. MiRNA, the small player, may play a hub role in connecting circadian rhythms and other pathways via its multiple target genes networks

    High Autophagy in the Naked Mole Rat may Play a Significant Role in Maintaining Good Health

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    Background/Aims: The maximum lifespan of the naked mole rat is over 28.3 years, which exceeds that of any other rodent species, suggesting that age-related changes in its body composition and functionality are either attenuated or delayed in this extraordinarily long-lived species. However, the mechanisms underlying the aging process in this species are poorly understood. In this study, we investigated whether long-lived naked mole rats display more autophagic activity than short-lived mice. Methods: Hepatic stellate cells isolated from naked mole rats were treated with 50 nM rapamycin or 20 mM 3-methyladenine (3-MA) for 12 or 24 h. Expression of the autophagy marker proteins LC3-II and beclin 1 was measured with western blotting and immunohistochemistry. The induction of apoptosis was analyzed by flow cytometry. Results: Our results demonstrate that one-day-old naked mole rats have higher levels of autophagy than one-day-old short-lived C57BL/6 mice, and that both adult naked mole rats (eight months old) and adult C57BL/6 mice (eight weeks old) have high basal levels of autophagy, which may be an important mechanism inhibiting aging and reducing the risk of age-related diseases. Conclusion: Here, we report that autophagy facilitated the survival of hepatic stellate cells from the naked mole rat, and that treatment with 3-MA or rapamycin increased the ratio of apoptotic cells to normal hepatic stellate cells

    The Protective Role of Autophagy in Heterocephalus glaber Hepatic Stellate Cells Exposed to H2O2 or Nutritional Stress

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    Background/Aims: Naked mole rats (NMRs) survive and thrive in dark, dank environments with low levels of oxygen and poor quality nutrition. Their long lifespan is attributed to sustained good health and pronounced resistance to cancer. Physiological and biochemical processes, such as autophagy, may contribute to the successful aging of this exceptionally long-lived species. We demonstrated that NMRs have higher levels of autophagy than short-lived C57BL/6 mice, and this may play an important role in the maintenance of cellular protein quality and the defense of cells against intracellular and extracellular aggressors in NMRs. The present study assesses autophagy as a means for cells to flexibly respond to environmental changes (H2O2 treatment and a shortage of nutrients). Methods: Primary NMR HSCs were isolated from liver and treated with serum-free medium. Cells in the experimental group were incubated with different concentrations of hydrogen peroxide (H2O2) in the presence and / or absence of 3-MA (5 mM).The LC3-II/LC3-I ratio was determined by western blot analysis. Western blotting was performed to analyze the expression level of Beclin 1 protein. Apoptosis and cell-cycle progression were analyzed by flow cytometry. Results: Our data reveal that both poor quality nutrition and H2O2 treatment induces apoptosis and autophagy in NMR hepatic stellate cells(HSCs). Conclusion: NMR cells have the capacity to induce cell death through apoptosis and downregulate the energy consuming processes through inhibition of proliferation when they become superfluous or irreversibly damaged

    Involvement of Cholinergic Dysfunction and Oxidative Damage in the Effects of Simulated Weightlessness on Learning and Memory in Rats

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    The present study aimed to determine how the learning and memory gradually change with the prolonged hindlimb unloading (HU) treatment in rats. Different HU durations (7 d, 14 d, 21 d, and 28 d) in Sprague-Dawley (SD) rats were implemented. Cognitive function was assessed using the Morris water maze (MWM) and the shuttle box test. Additionally, parameters about cholinergic activity and oxidative stress were tested. Results showed that longer-than-14 d HU led to the inferior performances in the behavioral tasks. Besides, acetylcholine esterase (AChE) activity, malondialdehyde (MDA) level in brain, reactive oxygen species (ROS), and 8-hydroxy-2-deoxyguanosine (8-OHdG) concentrations of HU rats were significantly increased. Furthermore, choline acetyltransferase (ChAT), superoxide dismutase (SOD), and catalase (CAT) activity in brain were notably attenuated. Most of these effects were more pronounced after longer exposure (21 d and 28 d) to HU, although some indicators had their own characteristics of change. These results indicate that cholinergic dysfunction and oxidative damage were involved in the learning and memory impairments induced by longer-than-14 d HU. Moreover, the negative effects of HU tend to be augmented as the HU duration becomes longer. The results may be helpful to present possible biochemical targets for countermeasures development regarding the memory deficits under extreme environmental conditions

    Reactive mesoporous silica nanoparticles loaded with limonene for improving physical and mental health of mice at simulated microgravity condition

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    Astronauts are under high stress for a long time because of the microgravity condition, which leads to anxiety, affects their learning and memory abilities, and seriously impairs the health of astronauts. Aromatherapy can improve the physical and mental health of astronauts in a way that moisturizes them softly and silently. However, the strong volatility of fragrances and inconvenience of aroma treatment greatly limit their application in the field of spaceflight. In this study, reactive mesoporous silica nanoparticles were prepared to encapsulate and slowly release limonene. The limonene loaded nanoparticles were named limonene@mesoporous silica nanoparticles-cyanuric chloride (LE@MSNs-CYC). LE@MSNs-CYC were then applied to wallpaper to improve the convenience of aromatherapy. LE@MSNs-CYC could chemically react with the wallpaper, thus firmly adsorbed on the wallpaper. In the following, the mice were treated with hindlimb unloading (HU) to simulate a microgravity environment. The results showed that 28-day HU led to an increase in the level of anxiety and declines in learning, memory, and physical health in mice. LE@MSNs-CYC showed significant relief effects on anxiety, learning, memory, and physical health of HU treated mice. Subsequently, the molecular mechanisms were explored by hypothalamic-pituitary-adrenal axis related hormones, immune-related cytokines, learning, and memory-related neurotransmitters and proteins

    Microbiota–muscle/immune interactions in rhesus macaque under simulated microgravity revealed by integrated multi‐omics analysis

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    Abstract Background Long‐term exposure to microgravity during spaceflight has adverse effects on human health including muscle atrophy, impaired immune function, and alterations in gut microbiome profile. Gut microorganisms influence a wide range of host biological processes, but their interactions with skeletal muscle and the immune system under microgravity have yet to be elucidated. Methods Rhesus macaques (Macaca mulatta) were subjected to −6° head‐down tilted bed rest (HDBR) for 6 weeks. Faecal samples, skeletal muscle tissue, and peripheral blood mononuclear cells (PBMCs) were collected for metagenomic, metabolomic, and transcriptomic analyses, respectively, and further integrated for a multi‐omics analysis. Results Head‐down tilted bed rest significantly altered taxon abundance (P 1.2, variable importance in projection >1) in atrophied muscles, including some crucial metabolites (such as l‐alanine and l‐carnitine) and hub metabolites (such as pyridoxamine and epinephrine) involved in energy metabolism. Transcriptomic analysis of PBMCs revealed genes related to leucocyte activation, differentiation, and interleukin‐2 production that were differentially expressed as a result of HDBR exposure (fold change >2 and P < 0.05). By integrating multi‐omics analysis, we identified three bacterial genera (Klebsiella, Kluyvera, and Bifidobacterium) that were closely associated with immune dysfunction and five (including Oligella, Sporosarcina, Citrobacter, Weissella, and Myroides) that were associated with abnormal metabolism of amino acids in atrophied muscles induced by HDBR. The reduced abundance of butyrate‐producing colon bacteria Eubacterium, Roseburia, and their cross‐feeding bacteria Bifidobacteria may contribute to the impaired immune function and muscle atrophy caused by HDBR. Conclusions This is the first report of the HDBR‐associated changes in gut microbiota composition, metabolomics of skeletal muscle, and transcripts of PBMCs in a non‐human primate. The underlying microbiota–muscle and microbiota–immune interactions during simulated microgravity imply that modulation of gut microbiota may represent a novel strategy for enhancing the health and safety of crew members during long‐term space expeditions

    HuR-mediated nucleocytoplasmic translocation of HOTAIR relieves its inhibition of osteogenic differentiation and promotes bone formation

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    Abstract Bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and osteoblast function play critical roles in bone formation, which is a highly regulated process. Long noncoding RNAs (lncRNAs) perform diverse functions in a variety of biological processes, including BMSC osteogenic differentiation. Although several studies have reported that HOX transcript antisense RNA (HOTAIR) is involved in BMSC osteogenic differentiation, its effect on bone formation in vivo remains unclear. Here, by constructing transgenic mice with BMSC (Prx1-HOTAIR)- and osteoblast (Bglap-HOTAIR)-specific overexpression of HOTAIR, we found that Prx1-HOTAIR and Bglap-HOTAIR transgenic mice show different bone phenotypes in vivo. Specifically, Prx1-HOTAIR mice showed delayed bone formation, while Bglap-HOTAIR mice showed increased bone formation. HOTAIR inhibits BMSC osteogenic differentiation but promotes osteoblast function in vitro. Furthermore, we identified that HOTAIR is mainly located in the nucleus of BMSCs and in the cytoplasm of osteoblasts. HOTAIR displays a nucleocytoplasmic translocation pattern during BMSC osteogenic differentiation. We first identified that the RNA-binding protein human antigen R (HuR) is responsible for HOTAIR nucleocytoplasmic translocation. HOTAIR is essential for osteoblast function, and cytoplasmic HOTAIR binds to miR-214 and acts as a ceRNA to increase Atf4 protein levels and osteoblast function. Bglap-HOTAIR mice, but not Prx1-HOTAIR mice, showed alleviation of bone loss induced by unloading. This study reveals the importance of temporal and spatial regulation of HOTAIR in BMSC osteogenic differentiation and bone formation, which provides new insights into precise regulation as a target for bone loss
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