FOS
Proto-oncogene c-Fos (Cellular oncogene fos) (G0/G1 switch regulatory protein 7) [G0S7]
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In mammals, microRNAs can be actively secreted from cells to blood. miR-29b-3p has been shown to play a pivotal role in muscle atrophy, but its role in intercellular communication is largely unknown. Here, we showed that miR-29b-3p was upregulated in normal and premature aging mouse muscle and plasma. miR-29b-3p was also upregulated in the blood of aging individuals, and circulating levels of miR-29b-3p were negatively correlated with relative appendicular skeletal muscle. Consistently, miR-29b-3p was observed in exosomes isolated from long-term differentiated atrophic C2C12 cells. When C2C12-derived miR-29b-3p-containing exosomes were uptaken by neuronal SH-SY5Y cells, increased miR-29b-3p levels in recipient cells were observed. Moreover, miR-29b-3p overexpression led to downregulation of neuronal-related genes and inhibition of neuronal differentiation. Interestingly, we identified HIF1α-AS2 as a novel c-FOS targeting lncRNA that is induced by miR-29b-3p through down-modulation of c-FOS and is required for miR-29b-3p-mediated neuronal differentiation inhibition. Our results suggest that atrophy-associated circulating miR-29b-3p may mediate distal communication between muscle cells and neurons.
Keywords
- HIF-1α-AS2
- aging
- lncRNAs
- miR-29b-3p
- muscle atrophy
The long noncoding RNA GUARDIN functions to protect genome stability. Inhibiting GUARDIN expression can alter cell fate decisions toward senescence or apoptosis, but the underlying molecular signals are unknown. Here, we show that GUARDIN is an essential component of a transcriptional repressor complex involving LRP130 and PGC1α. GUARDIN acts as a scaffold to stabilize LRP130/PGC1α heterodimers and their occupancy at the FOXO4 promotor. Destabilizing this complex by silencing of GUARDIN, LRP130, or PGC1α leads to increased expression of FOXO4 and upregulation of its target gene p21, thereby driving cells into senescence. We also found that GUARDIN expression was induced by rapamycin, an agent that suppresses cell senescence. FOS-like antigen 2 ([[FOSL2]]) acts as a transcriptional repressor of GUARDIN, and lower [[FOSL2]] levels in response to rapamycin correlate with increased levels of GUARDIN. Together, these results demonstrate that GUARDIN inhibits p21-dependent senescence through a LRP130-PGC1α-FOXO4 signaling axis, and moreover, GUARDIN contributes to the anti-aging activities of rapamycin.
Keywords
GUARDIN
- LRP130-PGC1α
- cellular senescence
- lncRNAs
- p21
Gut microbiota improved using prebiotics may delay the onset of senescence-related health problems. We hypothesized that prolonged intake of prebiotics delays senile osteoporosis. Forty-five male senescence-accelerated mouse prone 6 (SAMP6) aged four weeks were raised on 5% fructooligosaccharide (FOS), 5% glucomannan (GM), or a control diet for 31 weeks. Gut microbiota were identified using culture-dependent analytical methods. Mineral content in femoral bone was analyzed using atomic absorption spectrophotometry. Bone metabolism and inflammatory markers were measured using enzyme-linked immunosorbent assay. The numbers of Lactobacillus and Bacteroides in cecal contents were significantly higher in the FOS than in the control group ( p < 0.05); the number of Clostridium was significantly higher in the GM than in the control group ( p < 0.05). Calcium content was significantly higher in the femoral bones of the FOS group (30.5 ± 0.8 mg) than in the control group (27.5 ± 1.5 mg) ( p < 0.05). There was no difference between the GM (29.1 ± 2.0 mg) and control groups. During senescence, urinary deoxypyridinoline and serum high-sensitivity C-reactive protein levels significantly decreased in the FOS (1.2 ± 0.2 nmol/3 d and 80 ± 6.1 ng/100 mL) and GM groups (1.2 ± 0.2 nmol/3 d and 80 ± 6.1 ng/100 mL) compared with the control group (1.8 ± 0.5 nmol/3 d and 93 ± 7.4 ng/100 mL) ( p < 0.05). Thus, dietary FOS and GM modified gut microbiota and reduced bone resorption by reducing systemic inflammation in SAMP6.
MeSH Terms
- Aging
- Animals
- Bacteroides
- Bone and Bones
- C-Reactive Protein
- Disease Models, Animal
- Gastrointestinal Microbiome
- Humans
- Lactobacillus
- Male
- Mannans
- Mice
- Oligosaccharides
- Osteoporosis
- Prebiotics
Keywords
- SAMP6
- bone metabolism
- gut microbiota
- nondigestible saccharide
- prebiotics
Adaptogens are natural compounds or plant extracts that increase adaptability and survival of organisms under stress. Adaptogens stimulate cellular and organismal defense systems by activating intracellular and extracellular signaling pathways and expression of stress-activated proteins and neuropeptides. The effects adaptogens on mediators of adaptive stress response and longevity signaling pathways have been reported, but their stress-protective mechanisms are still not fully understood. The aim of this study was to identify key molecular mechanisms of adaptogenic plants traditionally used to treat stress and aging-related disorders, i.e., Rhodiola rosea, Eleutherococcus senticosus, Withania somnifera, Rhaponticum carthamoides, and Bryonia alba. To investigate the underlying molecular mechanisms of adaptogens, we conducted RNA sequencing to profile gene expression alterations in T98G neuroglia cells upon treatment of adaptogens and analyzed the relevance of deregulated genes to adaptive stress-response signaling pathways using in silico pathway analysis software. At least 88 of the 3516 genes regulated by adaptogens were closely associated with adaptive stress response and adaptive stress-response signaling pathways (ASRSPs), including neuronal signaling related to corticotropin-releasing hormone, cAMP-mediated, protein kinase A, and CREB; pathways related to signaling involving CXCR4, melatonin, nitric oxide synthase, GP6, Gαs, MAPK, neuroinflammation, neuropathic pain, opioids, renin-angiotensin, AMPK, calcium, and synapses; and pathways associated with dendritic cell maturation and G-coupled protein receptor-mediated nutrient sensing in enteroendocrine cells. All samples tested showed significant effects on the expression of genes encoding neurohormones CRH, GNRH, UCN, G-protein-coupled and other transmembrane receptors TLR9, PRLR, CHRNE, GP1BA, PLXNA4, a ligand-dependent nuclear receptor RORA, transmembrane channels, transcription regulators FOS, FOXO6, SCX, STAT5A, ZFPM2, ZNF396, ZNF467, protein kinases MAPK10, MAPK13, MERTK, FLT1, PRKCH, ROS1, TTN), phosphatases PTPRD, PTPRR, peptidases, metabolic enzymes, a chaperone (HSPA6), and other proteins, all of which modulate numerous life processes, playing key roles in several canonical pathways involved in defense response and regulation of homeostasis in organisms. It is for the first time we report that the molecular mechanism of actions of melatonin and plant adaptogens are alike, all adaptogens tested activated the melatonin signaling pathway by acting through two G-protein-coupled membrane receptors MT1 and MT2 and upregulation of the ligand-specific nuclear receptor RORA, which plays a role in intellectual disability, neurological disorders, retinopathy, hypertension, dyslipidemia, and cancer, which are common in aging. Furthermore, melatonin activated adaptive signaling pathways and upregulated expression of UCN, GNRH1, TLR9, GP1BA, PLXNA4, CHRM4, GPR19, VIPR2, RORA, STAT5A, ZFPM2, ZNF396, FLT1, MAPK10, MERTK, PRKCH, and TTN, which were commonly regulated by all adaptogens tested. We conclude that melatonin is an adaptation hormone playing an important role in regulation of homeostasis. Adaptogens presumably worked as eustressors ("stress-vaccines") to activate the cellular adaptive system by inducing the expression of ASRSPs, which then reciprocally protected cells from damage caused by distress. Functional investigation by interactive pathways analysis demonstrated that adaptogens activated ASRSPs associated with stress-induced and aging-related disorders such as chronic inflammation, cardiovascular health, neurodegenerative cognitive impairment, metabolic disorders, and cancer. This study has elucidated the genome-wide effects of several adaptogenic herbal extracts in brain cells culture. These data highlight the consistent activation of ASRSPs by adaptogens in T98G neuroglia cells. The extracts affected many genes playing key roles in modulation of adaptive homeostasis, indicating their ability to modify gene expression to prevent stress-induced and aging-related disorders. Overall, this study provides a comprehensive look at the molecular mechanisms by which adaptogens exerts stress-protective effects.
MeSH Terms
- Adaptation, Physiological
- Brain
- Bryonia
- Cell Line, Tumor
- Eleutherococcus
- Glioblastoma
- Humans
- Leuzea
- Longevity
- Neuroglia
- Plant Extracts
- Rhodiola
- Signal Transduction
- Systems Biology
- Withania
Keywords
- Adaptogen
- Melatonin
- Pathway analysis
- RNA sequencing
- Rhodiola
- Withania
Adolescence is accompanied by the maturation of several stress-responsive areas of the brain including the amygdala, a key region for the acquisition and expression of conditioned fear. These changes may contribute to the development of stress-related disorders in adolescence, such as anxiety and depression, and increase the susceptibility to these psychopathologies later in life. Here, we assessed the effects of acute restraint stress on fear learning and amygdala activation in pre-adolescent and adult male rats. Pre-adolescents exposed to stress prior to fear conditioning showed greater resistance to the extinction of fear memories than adults. At the cellular level, the combination of stress and fear conditioning resulted in a greater number of FOS-positive cells in the basolateral nucleus of the amygdala (BLA) than fear conditioning alone, and this increase was greater in pre-adolescents than in adults. Despite age-dependent differences, we found no changes in glucocorticoid receptor (GR) levels in the amygdala of either pre-adolescent or adult males. Overall, our data indicate that stress prior to fear conditioning leads to extinction-resistant fear responses in pre-adolescent animals, and that the BLA may be one neural locus mediating these age-dependent effects of stress on fear learning.
MeSH Terms
- Aging
- Amygdala
- Animals
- Anxiety
- Conditioning, Psychological
- Extinction, Psychological
- Fear
- Learning
- Male
- Memory
- Rats, Sprague-Dawley
- Receptors, Glucocorticoid
- Stress, Physiological
Keywords
- FOS
- amygdala
- fear conditioning
- glucocorticoid receptors
- restraint stress
The number of oocytes obtained from lambs after FSH treatment is far greater than those acquired from adult ewes. However, these oocytes typically have reduced viability in comparison with adult ewe oocytes. However, the molecular mechanisms of differences in viability between lamb and ewe oocytes remain unknown. In the present research, we applied iTRAQ coupled with LC-MS/MS proteomic analysis in order to investigate the proteomic expression profile of granulosa cells from lambs and ewes following stimulation with FSH. We detected 5649 proteins; 574 were differentially expressed between adults and juveniles. Based on Gene Ontology enrichment and KEGG pathway analysis, the majority of DEPs are participated in metabolic processes, ribosome and MAPK signaling pathways. Expression levels in ewes turned out to be lower than lambs. Protein interaction network analysis generated by STRING identified MAPK1, SMAD2, SMAD4, CDK1, FOS and ATM as the major findings among 54 significant differentially expressed of proteins. Quantitative real-time PCR analysis was applied to verify the proteomic analysis. These proteins which were identified in lambs may contribute to the reduction of oocyte quality compared to adults. The present research provides understanding of the molecular mechanism for follicle development in lambs.
MeSH Terms
- Aging
- Animals
- Embryo Transfer
- Female
- Fertility
- Fertilization in Vitro
- Follicle Stimulating Hormone
- Granulosa Cells
- Oocytes
- Proteomics
- Real-Time Polymerase Chain Reaction
- Sexual Maturation
- Sheep, Domestic
- Transcriptome
Keywords
- Granulosa cells
- Lamb
- Proteomics
- iTRAQ
During adolescence, the increased susceptibility to stress-related dysfunctions (e.g., anxiety, drug use, obesity) may be influenced by changes in the hormonal stress response mediated by the hypothalamic-pituitary-adrenal (HPA) axis. We have previously reported that restraint stress leads to significantly prolonged HPA responses in pre-adolescent compared to adult rats. Further, pre-adolescent animals exposed to restraint show greater levels of neural activation than adults in the paraventricular nucleus of the hypothalamus (PVN), a key nucleus integrating information from brain regions that coordinate HPA responses. Here, we examined the potential contribution of the noradrenergic A2 region of the nucleus of the solitary tract (NST) as a contributor to these age-dependent shifts in HPA reactivity. Specifically, we used double-labeled immunohistochemistry for FOS and dopamine-β-hydroxylase (DβH) to measure cellular activation and noradrenergic cells, respectively, before or after restraint stress in pre-adolescent (30days old) and adult (70days old) male rats. We also measured the density of DβH-immunoreactive fibers in the PVN as an index of noradrenergic inputs to this area. We found that pre-adolescent animals have a greater number of DβH-positive cells in the A2 region compared to adults, yet the number and percentage of double-labeled DβH/FOS cells were similar between these two ages. We found no differences between the ages in the staining intensity of DβH-immunoreactive fibers in the PVN. These data indicate there are adolescent-related changes in the number of noradrenergic cells in the A2 region, but no clear association between the increased stress reactivity prior to pubertal maturation and activation of A2 noradrenergic afferents to the PVN.
MeSH Terms
- Adrenergic Neurons
- Adrenocorticotropic Hormone
- Aging
- Animals
- Hypothalamo-Hypophyseal System
- Hypothalamus
- Male
- Pituitary-Adrenal System
- Rats, Sprague-Dawley
- Rhombencephalon
Keywords
- Adolescence
- Dopamine-beta-hydroxylase
- Nucleus of the solitary tract
- Puberty
- Restraint stress
The aim of this study was to investigate the relationship between fructooligosaccharide (FOS) intake at different life stages of Wistar rats and its stimulatory effects on intestinal parameters. Recently weaned and ageing female rats were divided into growing and ageing treatments, which were fed diets that partially replaced sucrose with FOS for 12 weeks. Dietary FOS intake induced a significant increase in the numbers of Bifidobacterium and Lactobacillus in growing rats. FOS intake was associated with increased butyric acid levels and a reduced pH of the caecal contents at both ages. Differential gene expression patterns were observed by microarray analysis of growing and ageing animals fed the FOS diet. A total of 133 genes showed detectable changes in expression in the growing rats, while there were only 19 gene expression changes in ageing rats fed with FOS. These results suggest that dietary FOS intake may be beneficial for some parameters of intestinal health in growing rats.
MeSH Terms
- Aging
- Animals
- Belgium
- Female
- Intestinal Mucosa
- Oligosaccharides
- Rats
- Rats, Wistar
Keywords
- Ageing
- Gene expression
- Intestinal health
- Prebiotic
- Youth
JNK proteins are conserved stress-activated MAP kinases. In C. elegans, the JNK-homolog KGB-1 plays essential roles in protection from heavy metals and protein folding stress. However, the contributions of KGB-1 are age-dependent, providing protection in larvae, but reducing stress resistance and shortening lifespan in adults. Attenuation of DAF-16 was linked to the detrimental contributions of KGB-1 in adults, but its involvement in KGB-1-dependent protection in larvae remains unclear. To characterize age-dependent contributions of KGB-1, we used microarray analysis to measure gene expression following KGB-1 activation either in developing larvae or in adults, achieved by knocking down its negative phosphatase regulator vhp-1. This revealed a robust KGB-1 regulon, most of which consisting of genes induced following KGB-1 activation regardless of age; a smaller number of genes was regulated in an age-dependent manner. We found that the bZIP transcription factor FOS-1 was essential for age-invariant KGB-1-dependent gene induction, but not for age-dependent expression. The latter was more affected by DAF-16, which was further found to be required for KGB-1-dependent cadmium resistance in larvae. Our results identify FOS-1 as a transcriptional activator mediating age-invariant contributions of KGB-1, including a regulatory loop of KGB-1 signaling, but also stress the importance of DAF-16 as a mediator of age-dependent contributions.
MeSH Terms
- Aging
- Animals
- Cadmium
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Gene Expression Regulation
- Gene Ontology
- JNK Mitogen-Activated Protein Kinases
- Molecular Sequence Annotation
- Proto-Oncogene Proteins c-fos
- Regulon
- Sequence Homology, Amino Acid
- Signal Transduction
- Trans-Activators
Keywords
- Antagonistic pleiotropy
- Cadmium
- DAF-16
- FOS-1
- JNK
- KGB-1
IgA nephropathy(IgAN) is the most common primary glomerular disease in China. Primary infections always occur before IgAN. However, the pathology of IgAN is still unclear. Previously we found that LL37, a protein secreted by senescent cells, was specific for the progression of IgAN, and also played a role in the neutrophil function. So we hypothesized that the infiltration of neutrophils, inflammation factors, and aging markers , which were modulated by functional networks, induced the immune response and renal injury. RNA-Sequencing (RNA-seq) can be used to study the whole transcriptome and detect splicing variants that are expressed in a specific cell type or tissue. We separate glomerulus from the renal biopsy tissues. After RNA extraction, the sequences were analyzed with Illumina HiSeq 2000/2500. 381 genes with differential expression between the IgAN patients and the healthy controls were identified. Only PLAU, JUN, and FOS were related to DNA damage, telomere dysfunction-induced aging markers, neutrophil function and IgA nephropathy. The networks showed the possibility of these genes being connected. We conclude that DNA damage and telomere dysfunction could play important roles in IgA nephropathy. In addition, neutrophils are also important factors in this disease. The networks of these markers showed the mechanism pathways that are involved in the duration of the occurrence and progression of IgA nephropathy and might be a new therapeutic opportunity for disease treatment.
MeSH Terms
- Adult
- Aging
- Biomarkers
- Female
- Gene Expression Profiling
- Gene Regulatory Networks
- Glomerulonephritis, IGA
- Humans
- Male
- Middle Aged
- Transcriptome
Keywords
- IgAN
- Pathology Section
- RNA sequence
- aging
- glomerular
- networks
Vitamin E has been suggested as nutritional intervention for the prevention of degenerative and age-related diseases. In this study, we aimed to elucidate the underlying mechanism of tocotrienol-rich fraction (TRF) in delaying cellular aging by targeting the proliferation signaling pathways in human diploid fibroblasts (HDFs). Tocotrienol-rich fraction was used to treat different stages of cellular aging of primary human diploid fibroblasts viz. young (passage 6), pre-senescent (passage 15) and senescent (passage 30). Several selected targets involved in the downstream of PI3K/AKT and RAF/MEK/ERK pathways were compared in total RNA and protein. Different transcriptional profiles were observed in young, pre-senescent and senescent HDFs, in which cellular aging increased AKT, FOXO3, CDKN1A and RSK1 mRNA expression level, but decreased ELK1, FOS and SIRT1 mRNA expression level. With tocotrienol-rich fraction treatment, gene expression of AKT, FOXO3, ERK and RSK1 mRNA was decreased in senescent cells, but not in young cells. The three down-regulated mRNA in cellular aging, ELK1, FOS and SIRT1, were increased with tocotrienol-rich fraction treatment. Expression of FOXO3 and P21Cip1 proteins showed up-regulation in senescent cells but tocotrienol-rich fraction only decreased P21Cip1 protein expression in senescent cells. Tocotrienol-rich fraction exerts gene modulating properties that might be responsible in promoting cell cycle progression during cellular aging.
MeSH Terms
- Antioxidants
- Cell Proliferation
- Cells, Cultured
- Cellular Senescence
- Diploidy
- Fibroblasts
- Humans
- Tocotrienols
- Vitamin E
Keywords
- Cellular aging
- Gene expression
- Human diploid fibroblasts
- Tocotrienol-rich fraction
- Vitamin E